Tetracycline compounds

ABSTRACT

The present invention is directed to a compound represented by Structural Formula (I): 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof. The variables for Structural Formula I are defined herein. 
     Also described is a pharmaceutical composition comprising the compound of Structural Formula I and its therapeutic use.

RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.13/319,298, which is the U.S. National Stage of InternationalApplication No. PCT/US2010/001350, filed May 7, 2010, which designatedthe United States, published in English, and claims the benefit of U.S.Provisional Application No. 61/215,757, filed on May 8, 2009. The entireteachings of the above applications are incorporated herein byreference.

BACKGROUND OF THE INVENTION

The tetracyclines are broad spectrum anti-microbial agents that arewidely used in human and veterinary medicine. The total production oftetracyclines by fermentation or semi-synthesis is measured in thethousands of metric tons per year.

The widespread use of tetracyclines for therapeutic purposes has led tothe emergence of resistance to these antibiotics, even among highlysusceptible bacterial species. Therefore, there is need for newtetracycline analogs with improved antibacterial activities andefficacies against other tetracycline responsive diseases or disorders.

SUMMARY OF THE INVENTION

Compounds of Formula I are new tetracycline analogs with improvedantibacterial activities and efficacies against other tetracyclineresponsive diseases or disorders:

Pharmaceutically acceptable salts of the compound of Formula I are alsoincluded. Values for the variables in Formula I are provided below:

X is selected from hydrogen, bromo, fluoro, chloro, C₁-C₆ alkyl,—O—C₁-C₆ alkyl, —S(O)_(m)—C₁-C₆ alkyl, C₃-C₇ cycloalkyl, —O—C₃-C₇cycloalkyl, —S(O)_(m)—C₃-C₇ cycloalkyl, —CN, —N(R⁴)(R⁵), and—NH—C(O)—(C₁-C₆ alkylene)-N(R⁴)(R⁵), wherein each alkyl, alkylene orcycloalkyl in the group represented by X is optionally substituted withfluoro;

Y is selected from fluoro, —C₁-C₆ alkyl, and—[C(R^(1a))(R^(1b))]_(m)—N(R²)(R³);

Z is selected from hydrogen, fluoro, bromo, —CN,—[C(R^(1a))(R^(1b))]_(n)—N(R²)(R³), —N(R⁴)(R⁵), NO₂, —NH—C(O)—C₁-C₄alkylene-N(R⁴)(R⁵), C₁-C₆ alkyl, —NH—C(O)—C₁-C₆ alkyl,—NH—S(O)_(m)—C₁-C₆ alkyl, —NH—S(O)_(m)—C₃-C₁₀ carbocyclyl,—NH—S(O)_(m)—(4-13 membered) heterocyclyl;

each R^(1a) and R^(1b) is independently selected from hydrogen, C₁-C₄alkyl, and C₃-C₁₀ carbocyclyl;

R² is selected from hydrogen, C₁-C₁₂ alkyl, —C₀-C₆ alkylene-C₃-C₁₀carbocyclyl, and —C₀-C₆ alkylene-(4-13 membered) heterocyclyl;

R³ is selected from hydrogen, C₁-C₈ alkyl, —C₀-C₆ alkylene-C₃-C₁₀carbocyclyl, —C₀-C₆ alkylene-(4-13 membered) heterocyclyl, —C(O)—C₁-C₆alkyl, —C₀-C₆ alkylene-C(O)N(R⁴)(R⁵), —C(O)—C₁-C₆ alkylene-N(R⁴)(R⁵),—C₂-C₆ alkylene-N(R⁴)(R⁵), —S(O)_(m)—C₁-C₆ alkyl, —S(O)_(m)—C₃-C₁₀carbocyclyl, and —S(O)_(m)-(4-13 membered) heterocyclyl, wherein eachalkyl, carbocyclyl, alkylene or heterocyclyl in the group represented byR² or R³ is optionally and independently substituted with one or moresubstituents independently selected from fluoro, chloro, —OH, —O—C₁-C₄alkyl, C₁-C₄ alkyl, fluoro-substituted-C₁-C₄ alkyl, —N(R⁴)(R⁵), C₃-C₁₀carbocyclyl or a (4-13 membered) heterocyclyl; or

R² and R³ taken together with the nitrogen atom to which they are boundform a (4-7 membered) monocyclic heterocylic ring, or a (6-13 membered)bicyclic, spirocyclic or bridged heterocylic ring, wherein the (4-7membered) monocyclic heterocylic ring, or the (6-13 membered) bicyclic,spirocyclic or bridged heterocyclic ring optionally comprises 1 to 4additional heteroatoms independently selected from N, S and O; andwherein the (4-7 membered) monocyclic heterocylic ring, or the (6-13membered) bicyclic, spirocyclic or bridged heterocyclic ring isoptionally substituted with one or more substituents independentlyselected from C₃-C₁₀ carbocyclyl, (4-13 membered) heterocyclyl, fluoro,chloro, —OH, C₁-C₄ fluoroalkyl, C₁-C₄ alkyl, —O—C₃-C₁₀ carbocyclyl,—O-(4-13 membered) heterocyclyl, —C₀-C₄ alkyl-O—C₁-C₄ alkyl, —C₀-C₄alkyl-O—C₁-C₄ fluoroalkyl, ═O, —C(O)—C₁-C₄ alkyl, —C(O)N(R⁴)(R⁵),—N(R⁴)—C(O)—C₁-C₄ alkyl, and —C₀-C₄ alkylene-N(R⁴)(R⁵), and wherein eachcarbocyclyl or heterocyclyl substituent is optionally substituted withfluoro, chloro, —OH, C₁-C₄ fluoroalkyl, C₁-C₄ alkyl, —O—C₁-C₄ alkyl,—O—C₁-C₄ fluoroalkyl, —NH₂, —NH(C₁-C₄ alkyl), or —N(C₁-C₄ alkyl)₂;

each of R⁴ and R⁵ is independently selected from hydrogen and C₁-C₄alkyl; or

R⁴ and R⁵ taken together with the nitrogen atom to which they are boundform a (4-7 membered) heterocylic ring optionally comprising oneadditional heteroatom selected from N, S and O, wherein the (4-7membered) heterocylic ring is optionally substituted with fluoro,chloro, —OH, fluoro-substituted C₁-C₄ alkyl, —C₁-C₄ alkyl, or —C₁-C₄alkylene-O—C₁-C₄ alkyl, and is optionally benzofused;

m is 0, 1 or 2; and

n is 1 or 2,

with the proviso that when Z is —NH—C(O)—C₁-C₄ alkyl-N(R⁴)(R⁵), X isother than fluoro.

Another embodiment of the present invention is directed to apharmaceutical composition comprising a pharmaceutically acceptablecarrier or diluent and a compound disclosed herein or a pharmaceuticallyacceptable salt thereof. The pharmaceutical composition is used intherapy, such as treating an infection in a subject.

Another embodiment of the present invention is a method of treating aninfection in a subject comprising administering to the subject aneffective amount of a compound disclosed herein or a pharmaceuticallyacceptable salt thereof.

Another embodiment of the present invention is the use of a compounddisclosed herein or a pharmaceutically acceptable salt thereof for themanufacture of a medicament for treating an infection in a subject.

Another embodiment of the present invention is the use of a compounddisclosed herein or a pharmaceutically acceptable salt thereof fortherapy, such as treating an infection in a subject.

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1A-1C provide MIC values for the indicated compound.

FIGS. 2A-2K provide compounds in accordance with Structure Formula I.

FIGS. 3A-3EE provide compounds in accordance with Structure Formula I.

FIGS. 4A-4Z provide compounds in accordance with Structure Formula I.

FIGS. 5A-5O provide compounds in accordance with Structure Formula I.

FIGS. 6A-6FF provide compounds in accordance with Structure Formula I.

FIGS. 7A-7J provide MIC values for compounds of the invention.

FIGS. 8A-8D provide MIC values for compounds of the invention.

FIGS. 9A-9M provide MIC values for compounds of the invention.

FIGS. 10A-10I provide MIC values for compounds of the invention.

FIGS. 11A-11G provide MIC values for compounds of the invention.

The foregoing will be apparent from the following more particulardescription of example embodiments of the invention, as illustrated inthe accompanying drawings in which like reference characters refer tothe same parts throughout the different views. The drawings are notnecessarily to scale, emphasis instead being placed upon illustratingembodiments of the present invention.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is directed to a compound represented byStructural Formula I or a pharmaceutically acceptable salt thereof.Values and alternative values for the variables in Structural Formula Iare defined as the following:

X is hydrogen, bromo, fluoro, chloro, C₁-C₆ alkyl, —O—C₁-C₆ alkyl,—S(O)_(m)—C₁-C₆ alkyl, C₃-C₇ cycloalkyl, —O—C₃-C₇ cycloalkyl,—S(O)_(m)—C₃-C₇ cycloalkyl, —CN, —N(R⁴)(R⁵) or —NH—C(O)—(C₁-C₆alkylene)-N(R⁴)(R⁵). Each alkyl, alkylene or cycloalkyl in the grouprepresented by X is optionally substituted with fluoro. In anotherembodiment, X is fluoro, chloro, —CN or —N(CH₃)₂. Alternatively, X isfluoro, chloro or —N(CH₃)₂. In another alternative, X is fluoro. In yetanother alternative, X is chloro. In yet another alternative, X is—N(CH₃)₂. In yet another embodiment, X is hydrogen. In still anotherembodiment when Z is —NH—C(O)—C₁-C₄ alkyl-N(R⁴)(R⁵), X is other thanfluoro.

Y is fluoro, —C₁-C₆ alkyl, or —[C(R^(1a))(R^(1b))]_(m)—N(R²)(R³). Inanother embodiment, Y is fluoro, methyl, —CH(R^(1a))—N(R²)(R³),—(CH₂)₂—N(R²)(R³), —NH(pyridyl), —NH—(C₁-C₈ alkyl), —NHC(O)—C₁-C₃alkylene-piperidine, —NHC(O)—C₁-C₃ alkylene-pyrrolidine or—NHS(O)₂-phenyl, wherein each piperidine and each pyrrolidine in thegroup represented by Y is optionally substituted with one or more —C₁-C₆alkyl. In another embodiment, Y is fluoro, methyl or—CH(R^(1a))—N(R²)(R³). Alternatively, Y is —CH(R^(1a))—N(R²)(R³). Inanother alternative, Y is fluoro. In yet another alternative, Y is—NHR³.

Z is hydrogen, fluoro, bromo, —CN, —[C(R^(1a))(R^(1b))]_(n)—N(R²)(R³),—N(R⁴)(R⁵), NO₂, —NH—C(O)—C₁-C₄ alkylene-N(R⁴)(R⁵), C₁-C₆ alkyl,—NH—C(O)—C₁-C₆ alkyl, —NH—S(O)_(m)—C₁-C₆ alkyl, —NH—S(O)_(m)—C₃-C₁₀carbocyclyl or —NH—S(O)_(m)-(4-13 membered) heterocyclyl. In anotherembodiment, Z is hydrogen, NH₂ or —CH₂—NH—CH₂—C(CH₃)₃. In anotherembodiment, Z is hydrogen. Alternatively, Z is—[C(R^(1a))(R^(1b))]_(n)—N(R²)(R³) or —N(R⁴)(R⁵).

Each R^(1a) and R^(1b) is independently hydrogen, C₁-C₄ alkyl or C₃-C₁₀carbocyclyl. In another alternative. R^(1a) is hydrogen or methyl.

-   -   R² is hydrogen, C₁-C₁₂ alkyl, —C₀-C₆ alkylene-C₃-C₁₀        carbocyclyl, and —C₀-C₆ alkylene-(4-13 membered) heterocyclyl.        Each alkyl, carbocyclyl, alkylene or heterocyclyl in the group        represented by R² is optionally and independently substituted        with one or more substituents independently selected from        fluoro, chloro, —OH, —O—C₁-C₄ alkyl, C₁-C₄ alkyl,        fluoro-substituted-C₁-C₄ alkyl, —N(R⁴)(R⁵), C₃-C₁₀ carbocyclyl        and a (4-13 membered) heterocyclyl. In another alternative, R²        is hydrogen, C₁-C₃ straight chained alkyl, C₁-C₃ straight        chained fluoroalkyl, cyclopropyl or —CH₂-cyclopropyl.        Alternatively, R² is hydrogen, C₁-C₃ straight chained alkyl or        —CH₂-cyclopropyl.    -   R³ is hydrogen, C₁-C₈ alkyl, —C₀-C₆ alkylene-C₃-C₁₀ carbocyclyl,        —C₀-C₆ alkylene-(4-13 membered) heterocyclyl, —C(O)—C₁-C₆ alkyl,        —C₀-C₆ alkylene-C(O)N(R⁴)(R⁵), —C(O)—C₁-C₆ alkylene-N(R⁴)(R⁵),        —C₂-C₆ alkylene-N(R⁴)(R⁵), —S(O)_(m)—C₁-C₆ alkyl,        —S(O)_(m)—C₃-C₁₀ carbocyclyl or —S(O)_(m)-(4-13 membered)        heterocyclyl. When R² is hydrogen or C₁-C₂ alkyl, R³ is        additionally benzyl. Each alkyl, carbocyclyl, alkylene or        heterocyclyl in the group represented by R³ is optionally and        independently substituted with one or more substituents        independently selected from fluoro, chloro, —O—OH, —O—C₁-C₄        alkyl, C₁-C₄ alkyl, fluoro-substituted-C₁-C₄ alkyl, —N(R⁴)(R⁵),        C₃-C₁₀ carbocyclyl and a (4-13 membered) heterocyclyl. In        another alternative, R³ is hydrogen, C₁-C₈ alkyl, —CH₂—CHF₂,        —C₂-C₆ alkylene-O—C₁-C₃ alkyl, —C₃-C₁₀ cycloalkyl, —C₃-C₁₀        cycloalkyl-substituted C₁-C₃ alkyl, cyclopropyl-substituted        cyclopropyl, —(CH₂)₂-phenyl or —S(O)₂-phenyl. Alternatively, R³        is hydrogen, C₁-C₈ alkyl, —CH₂—CHF₂, —C₁-C₆ alkylene-O—C₁-C₃        alkyl, C₃-C₁₀ cycloalkyl, C₃-C₁₀ cycloalkyl-substituted C₁-C₃        alkyl, —(CH₂)₂-phenyl, and when R² is hydrogen or —C₁-C₂ alkyl,        R³ is additionally benzyl. In another embodiment, R³ is selected        from hydrogen, C₁-C₈ alkyl, —CH₂—CHF₂, —C₁-C₆ alkylene-O—C₁-C₃        alkyl, C₃-C₁₀ cycloalkyl, —(CH₂)₂-phenyl and C₃-C₁₀        cycloalkyl-substituted C₁-C₃ alkyl, wherein each cycloalkyl in        the group represented by R³ is optionally substituted with        —C₁-C₃ alkyl or optionally benzofused.

Alternatively, R² and R³ taken together with the nitrogen atom to whichthey are bound form a (4-7 membered) monocyclic heterocylic ring, or a(6-13 membered) bicyclic, spirocyclic or bridged heterocylic ring,wherein the (4-7 membered) monocyclic heterocylic ring, or the (6-13membered) bicyclic, spirocyclic or bridged heterocyclic ring optionallycomprises 1 to 4 additional heteroatoms independently selected from N, Sand O. The (4-7 membered) monocyclic heterocylic ring, or the (6-13membered) bicyclic, spirocyclic or bridged heterocyclic ring isoptionally substituted with one or more substituents independentlyselected from C₃-C₁₀ carbocyclyl, (4-13 membered) heterocyclyl, fluoro,chloro, —OH, C₁-C₄ fluoroalkyl, C₁-C₄ alkyl, —O—C₃-C₁₀ carbocyclyl,—O-(4-13 membered) heterocyclyl, —C₀-C₄ alkyl-O—C₁-C₄ alkyl, —C₀-C₄alkyl-O—C₁-C₄ fluoroalkyl, ═O, —C(O)—C₁-C₄ alkyl, —C(O)N(R⁴)(R⁵),—N(R⁴)—C(O)—C₁-C₄ alkyl, and —C₀-C₄ alkylene-N(R⁴)(R⁵), and wherein eachcarbocyclyl or heterocyclyl substituent is optionally substituted withfluoro, chloro, —OH, C₁-C₄ fluoroalkyl, C₁-C₄ alkyl, —O—C₁-C₄ alkyl,—O—C₁-C₄ fluoroalkyl, —NH₂, —NH(C₁-C₄ alkyl), or —N(C₁-C₄ alkyl)₂. Inanother embodiment, R² and R³ taken together with the nitrogen atom towhich they are bound form a ring selected from pyrrolidine, piperidine,piperazine or morpholine, wherein the ring is optionally substitutedwith one or more substituents independently selected from —OH, —C₁-C₃alkyl and —C₁-C₃ alkylene-O—C₁-C₃ alkyl, and wherein the ring isoptionally benzofused or spirofused to cyclopropyl. Alternatively, R²and R³ taken together with the nitrogen atom to which they are boundform a ring selected from pyrrolidine and piperidine, wherein the ringis optionally substituted with one or more substituents independentlyselected from fluoro, C₁-C₃ alkyl and —C₁-C₃ alkylene-O—C₁-C₃ alkyl, andwherein the ring is optionally benzofused or spirofused to cyclopropyl.

Each of R⁴ and R⁵ is independently hydrogen or C₁-C₄ alkyl.

Alternatively, R⁴ and R⁵ taken together with the nitrogen atom to whichthey are bound formula (4-7 membered) heterocylic ring optionallycomprising one additional heteroatom selected from N, S and O, whereinthe (4-7 membered) heterocylic ring is optionally substituted withfluoro, chloro, —OH, fluoro-substituted C₁-C₄ alkyl, —C₁-C₄ alkyl, or—C₁-C₄ alkylene-O—C₁-C₄ alkyl, and is optionally benzofised.

Each m is independently 0, 1 or 2.

n is 1 or 2.

In a second embodiment, the compound of the present invention isrepresented by Structural Formula I or a pharmaceutically acceptablesalt thereof wherein, Y is fluoro, methyl, —CH(R^(1a))—N(R²)(R³),—(CH₂)₂—N(R²)(R³), —NH(pyridyl), —NH(C₁-C₈ alkyl), —NHC(O)—C₁-C₃alkylene-piperidine, —NHC(O)—C₁-C₃ alkylene-pyrrolidine or—NHS(O)₂-phenyl, and each piperidine and each pyrrolidine in the grouprepresented by Y is optionally substituted with one or more —C₁-C₆alkyl; R^(1a) is hydrogen or methyl; R² is hydrogen, C₁-C₃ straightchained alkyl, C₁-C₃ straight chained fluoroalkyl, cyclopropyl or—CH₂-cyclopropyl; R³ is hydrogen, C₁-C₈ alkyl, —CH₂—CHF₂, —C₂-C₆alkylene-O—C₁-C₃ alkyl, —C₃-C₁₀ cycloalkyl, —C₃-C₁₀cycloalkyl-substituted C₁-C₃ alkyl, cyclopropyl-substituted cyclopropyl,—(CH₂)₂-phenyl or —S(O)₂-phenyl, and when R² is hydrogen or C₁-C₂ alkyl,R³ is additionally benzyl; or R² and R³ taken together with the nitrogenatom to which they are bound form a ring selected from pyrrolidine,piperidine, piperazine or morpholine, wherein the ring is optionallysubstituted with one or more substituents independently selected from—OH, —C₁-C₃ alkyl and —C₁-C₃ alkylene-O—C₁-C₃ alkyl, and wherein thering is optionally benzofused or spirofused to cyclopropyl; and valuesand alternative values for the remainder of the variables are asdescribed above.

In a third embodiment, the compound of the present invention isrepresented by Structural Formula I or a pharmaceutically acceptablesalt thereof wherein, Y is fluoro, methyl or —CH(R^(1a))—N(R²)(R³);R^(1a) is hydrogen or methyl; R² is hydrogen, C₁-C₃ straight chainedalkyl or —CH₂-cyclopropyl; R³ is hydrogen, C₁-C₈ alkyl, —CH₂—CHF₂,—C₁-C₆ alkylene-O—C₁-C₃ alkyl, C₃-C₁₀ cycloalkyl, C₃-C₁₀cycloalkyl-substituted C₁-C₃ alkyl, wherein each cycloalkyl in the grouprepresented by R³ is optionally substituted with —C₁-C₃ alkyl oroptionally benzofused, or —(CH₂)₂-phenyl, and when R² is hydrogen or—C₁-C₂ alkyl, R³ is additionally benzyl; or R² and R³ taken togetherwith the nitrogen atom to which they are bound form a ring selected frompyrrolidine and piperidine, wherein the ring is optionally substitutedwith one or more substituents independently selected from fluoro, —C₁-C₃alkyl and —C₁-C₃ alkylene-O—C₁-C₃ alkyl, and wherein the ring isoptionally benzofused or spirofused to cyclopropyl; and values andalternative values for the remainder of the variables are as describedabove.

In a fourth embodiment the compound of the present invention isrepresented by Structural Formula I or a pharmaceutically acceptablesalt thereof wherein, X is fluoro, chloro, —CN or —N(CH₃)₂; Z ishydrogen, NH₂ or —CH₂—NH—CH₂—C(CH₃)₃; and values and alternative valuesfor the remainder of the variables are as described above for StructuralFormula I or for the second or third embodiment.

In another embodiment of a compound of Formula I:

X is selected from —OCH₃, —CF₃, Cl, F, and —N(CH3)₂;

-   -   Z is hydrogen and when X is F, Z is additionally selected from        —NH₂, —NH(C₁-C₂ alkyl), and —N(C₁-C₂ alkyl)₂; and

Y is —CH₂—NR²R³; wherein

-   -   R² is selected from hydrogen, and C₁-C₃ alkyl; and

R³ is selected from hydrogen, C₁-C₅ alkyl, C₀-C₆ alkylene C₃-C₁₀carbocyclyl, C₀-C₆ alkylene-(4-13 membered) heterocyclyl, and C₂-C₆alkylene —N(R⁴)(R⁵), wherein each carbocyclyl or heterocyclyl in thegroup represented by R³ is optionally and independently substituted withone or more substituents independently selected from fluoro, —OH,—O—C₁-C₃ alkyl, C₁-C₃ alkyl, fluoro-substituted C₁-C₃ alkyl, —N(R⁴)(R⁵),C₃-C₁₀ carbocyclyl or a (4-13 membered) heterocyclyl; or

R² and R³ taken together with the nitrogen atom to which they are boundform a (4-7 membered) saturated monocyclic heterocylic ring, or a (6-13membered) saturated bicyclic, spirocyclic or bridged heterocylic ring,wherein the (4-7 membered) monocyclic heterocylic ring, or the (6-13membered) bicyclic, spirocyclic or bridged heterocyclic ring isoptionally substituted with one or more substituents independentlyselected from C₃-C₁₀ carbocyclyl, (4-13 membered) heterocyclyl, fluoro,—OH, —C₁-C₃ fluoroalkyl, —C₁-C₃ alkyl, O—C₃-C₁₀ carbocyclyl, O-(4-13membered) heterocyclyl, C₀-C₂alkylene-O—C₁-C₃ alkyl, C₀-C₂alkylene-O—C₁-C₃ fluoroalkyl, ═O, and C₀-C₄ alkylene N(R⁴)(R⁵), andwherein each carbocyclyl or heterocyclyl substituent is optionallysubstituted with fluoro, —OH, C₁-C₃ fluoroalkyl, C₁-C₃ alkyl, —O—C₁-C₃alkyl, —O—C₁-C₃ fluoroalkyl, —NH₂, —NH(C₁-C₄ alkyl), or —N(C₁-C₄alkyl)₂; and

each of R¹ and R⁵ is independently selected from hydrogen and C₁-C₄alkyl.

In one specific aspect of this embodiment X is —OCH₃. In anotherspecific aspect, X is —CF₃. In still another specific aspect, X is —Cl.In another specific aspect, X is —F and Z is hydrogen. In anotherspecific aspect, X is —F and Z is selected from —NH₂, —NH(C₁-C₂ alkyl),and —N(C₁-C₂ alkyl)₂. In still another specific aspect X is —N(CH₃)₂.

A fifth embodiment is a compound of Structural Formulas II, III, IIIa orIV or a pharmaceutically acceptable salt thereof:

Values and alternative values for the variables in Structural FormulasII, III, IIIa and IV are as defined for Structural Formula I or in thesecond or in the third embodiment. Alternatively, values for thevariables in Structural Formula II are as defined in the fourthembodiment. In Structural Formula II, X is preferably fluoro, chloro or—N(CH₃)₂.

In a sixth embodiment, the compound of the present invention isrepresented by Structural Formula f or a pharmaceutically acceptablesalt thereof wherein, Y is —NHR³; R³ is pyridyl, C₁-C₈ alkyl,—C(O)—C₁-C₃ alkylene-piperidine or —C(O)—C₁-C₃ alkylene-pyrrolidine Eachpiperidine or pyrrolidine in the group represented by R³ is optionallysubstituted with one or more C₁-C₃ alkyl. Values and alternative valuesfor the remainder of the variables are as defined for Structural FormulaI above or in the second or in the third embodiment.

A seventh embodiment is a compound of Structural Formula V or apharmaceutically acceptable salt thereof:

and values and alternative values for the remainder of the variables areas defined in the preceding paragraph.

Specific examples of compounds of the invention are represented byStructural Formula II, wherein:

X is fluoro and —CH(R^(1a))—NR²R³ is

X is fluoro and —CH(R^(1a))—NR²R³ is

X is fluoro and —CH(R^(1a))—NR²R³ is

X is fluoro and —CH(R^(1a))—NR²R³ is

X is fluoro and —CH(R^(1a))—NR²R³ is

X is fluoro and —CH(R^(1a))—NR²R³ is

X is fluoro and —CH(R^(1a))—NR²R³ is

X is fluoro and —CH(R^(1a))—NR²R³ is

X is fluoro and —CH(R^(1a))—NR²R³ is

X is fluoro and —CH(R^(1a))—NR²R³ is

X is fluoro and —CH(R^(1a))—NR²R³ is

X is fluoro and —CH(R^(1a))—NR²R³ is

X is fluoro and —CH(R^(1a))—NR²R³ is

X is fluoro and —CH(R^(1a))—NR²R³ is

X is fluoro and —CH(R^(1a))—NR²R³ is

X is fluoro and —CH(R^(1a))—NR²R³ is

X is fluoro and —CH(R^(1a))—NR²R³ is

X is fluoro and —CH(R^(1a))—NR²R³ is

X is fluoro and —CH(R^(1a))—NR²R³ is

X is fluoro and —CH(R^(1a))—NR²R³ is

X is fluoro and —CH(R^(1a))—NR²R³ is

X is fluoro and —CH(R^(1a))—NR²R³ is

X is fluoro and —CH(R^(1a))—NR²R³ is

X is fluoro and —CH(R^(1a))—NR²R³ is

X is fluoro and —CH(R^(1a))—NR²R³ is

X is fluoro and —CH(R^(1a))—NR²R³ is

X is fluoro and —CH(R^(1a))—NR²R³ is

X is fluoro and —CH(R^(1a))—NR²R³ is

X is fluoro and —CH(R^(1a))—NR²R³ is

X is fluoro and —CH(R^(1a))—NR²R³ is

X is fluoro and —CH(R^(1a))—NR²R³ is

X is fluoro and —CH(R^(1a))—NR²R³ is

X is fluoro and —CH(R^(1a))—NR²R³ is

X is fluoro and —CH(R^(1a))—NR²R³ is

X is fluoro and —CH(R^(1a))—NR²R³ is

X is fluoro and —CH(R^(1a))—NR²R³ is

X is fluoro and —CH(R^(1a))—NR²R³ is

X is fluoro and —CH(R^(1a))—NR²R³ is

X is fluoro and —CH(R^(1a))—NR²R³ is

X is fluoro and —CH(R^(1a))—NR²R³ is

X is fluoro and —CH(R^(1a))—NR²R³ is

X is fluoro and —CH(R^(1a))—NR²R³ is

X is fluoro and —CH(R^(1a))—NR²R³ is

X is fluoro and —CH(R^(1a))—NR²R³ is

X is fluoro and —CH(R^(1a))—NR²R³ is

X is fluoro and —CH(R^(1a))—NR²R³ is

X is fluoro and —CH(R^(1a))—NR²R³ is

X is fluoro and —CH(R^(1a))—NR²R³ is

X is fluoro and —CH(R^(1a))—NR²R³ is

X is fluoro and —CH(R^(1a))—NR²R³ is

X is fluoro and —CH(R^(1a))—NR²R³ is

X is fluoro and —CH(R^(1a))—NR²R³ is

X is fluoro and —CH(R^(1a))—NR²R³ is

X is fluoro and —CH(R^(1a))—NR²R³ is

X is fluoro and —CH(R^(1a))—NR²R³ is

X is fluoro and —CH(R^(1a))—NR²R³ is

X is fluoro and —CH(R^(1a))—NR²R³ is

X is fluoro and —CH(R^(1a))—NR²R³ is

X is fluoro and —CH(R^(1a))—NR²R³ is

X is fluoro and —CH(R^(1a))—NR²R³ is

X is fluoro and —CH(R^(1a))—NR²R³ is

X is fluoro and —CH(R^(1a))—NR²R³ is

X is fluoro and —CH(R^(1a))—NR²R³ is

X is fluoro and —CH(R^(1a))—NR²R³ is

X is fluoro and —CH(R^(1a))—NR²R³ is

X is fluoro and —CH(R^(1a))—NR²R³ is

X is fluoro and —CH(R^(1a))—NR²R³ is

X is fluoro and —CH(R^(1a))—NR²R³ is

X is fluoro and —CH(R^(1a))—NR²R³ is

X is fluoro and —CH(R^(1a))—NR²R³ is

X is fluoro and —CH(R^(1a))—NR²R³ is

X is fluoro and —CH(R^(1a))—NR²R³ is

X is fluoro and —CH(R^(1a))—NR²R³ is

X is fluoro and —CH(R^(1a))—NR²R³ is

X is fluoro and —CH(R^(1a))—NR²R³ is

X is fluoro and —CH(R^(1a))—NR²R³ is

X is fluoro and —CH(R^(1a))—NR²R³ is

X is fluoro and —CH(R^(1a))—NR²R³ is

X is fluoro and —CH(R^(1a))—NR²R³ is

X is fluoro and —CH(R^(1a))—NR²R³ is

X is fluoro and —CH(R^(1a))—NR²R³ is

X is fluoro and —CH(R^(1a))—NR²R³ is

X is fluoro and —CH(R^(1a))—NR²R³ is

X is fluoro and —CH(R^(1a))—NR²R³ is

X is fluoro and —CH(R^(1a))—NR²R³ is

X is fluoro and —CH(R^(1a))—NR²R³ is

X is fluoro and —CH(R^(1a))—NR²R³ is

X is fluoro and —CH(R^(1a))—NR²R³ is

X is fluoro and —CH(R^(1a))—NR²R³ is

X is fluoro and —CH(R^(1a))—NR²R³ is

X is fluoro and —CH(R^(1a))—NR²R³ is

X is fluoro and —CH(R^(1a))—NR²R³ is

X is fluoro and —CH(R^(1a))—NR²R³ is

X is fluoro and —CH(R^(1a))—NR²R³ is

X is fluoro and —CH(R^(1a))—NR²R³ is

X is fluoro and —CH(R^(1a))—NR²R³ is

X is fluoro and —CH(R^(1a))—NR²R³ is

X is fluoro and —CH(R^(1a))—NR²R³ is

X is fluoro and —CH(R^(1a))—NR²R³ is

X is fluoro and —CH(R^(1a))—NR²R³ is

X is fluoro and —CH(R^(1a))—NR²R³ is

X is fluoro and —CH(R^(1a))—NR²R³ is

X is fluoro and —CH(R^(1a))—NR²R³ is

X is fluoro and —CH(R^(1a))—NR²R³ is

X is fluoro and —CH(R^(1a))—NR²R³ is

X is fluoro and —CH(R^(1a))—NR²R³ is

X is fluoro and —CH(R^(1a))—NR²R³ is

X is fluoro and —CH(R^(1a))—NR²R³ is

X is fluoro and —CH(R^(1a))—NR²R³ is

X is fluoro and —CH(R^(1a))—NR²R³ is

X is fluoro and —CH(R^(1a))—NR²R³ is

X is fluoro and —CH(R^(1a))—NR²R³ is

X is fluoro and —CH(R^(1a))—NR²R³ is

X is fluoro and —CH(R^(1a))—NR²R³ is

X is fluoro and —CH(R^(1a))—NR²R³ is

X is fluoro and —CH(R^(1a))—NR²R³ is

X is fluoro and —CH(R^(1a))—NR²R³ is

X is fluoro and —CH(R^(1a))—NR²R³ is

X is fluoro and —CH(R^(1a))—NR²R³ is

X is fluoro and —CH(R^(1a))—NR²R³ is

X is fluoro and —CH(R^(1a))—NR²R³ is

X is fluoro and —CH(R^(1a))—NR²R³ is

X is fluoro and —CH(R^(1a))—NR²R³ is

X is fluoro and —CH(R^(1a))—NR²R³ is

X is fluoro and —CH(R^(1a))—NR²R³ is

X is fluoro and —CH(R^(1a))—NR²R³ is

X is fluoro and —CH(R^(1a))—NR²R³ is

X is fluoro and —CH(R^(1a))—NR²R³ is

X is fluoro and —CH(R^(1a))—NR²R³ is

X is fluoro and —CH(R^(1a))—NR²R³ is

X is fluoro and —CH(R^(1a))—NR²R³ is

X is fluoro and —CH(R^(1a))—NR²R³ is

X is fluoro and —CH(R^(1a))—NR²R³ is

X is fluoro and —CH(R^(1a))—NR²R³ is

X is fluoro and —CH(R^(1a))—NR²R³ is

X is fluoro and —CH(R^(1a))—NR²R³ is

Other specific examples of compounds of the invention are represented byStructural Formulas IIIa, wherein:

—[C(R^(1a))(R^(1b))]_(n)—N(R²)(R³) is

Additional specific examples of compounds of the invention arerepresented by Structural Formula V, wherein:

R is

Additional specific examples of the compounds of the present inventionare represented by Structural Formula IVa and IVb, or a pharmaceuticallyacceptable salt thereof:

Methods of preparation of the exemplified compounds are provided inExemplification section.

DEFINITIONS

“Alkyl” means a saturated aliphatic branched or straight-chainmonovalent hydrocarbon radical having the specified number of carbonatoms. Thus, “(C₁-C₁₂) alkyl” means a radical having from 1-12 carbonatoms in a linear or branched arrangement. “(C₁-C₁₂)alkyl” includesmethyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl,decyl, undecyl and dodecyl. Unless otherwise specified, suitablesubstitutions for a “substituted alkyl” include halogen, —OH, —O—C₁-C₄alkyl, C₁-C₄ alkyl, fluoro-substituted-C₁-C₄ alkyl, —O—C₁-C₄fluoroalkyl, —NH₂, —NH(C₁-C₄ alkyl), —N(C₁-C₄ alkyl)₂, C₃-C₁₀carbocyclyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,phenyl or naphthalenyl), a (4-13 membered) heterocyclyl (e.g.,pyrrolidine, piperidine, piperazine, tetrahydrofuran, tetrahydropyran ormorpholine) or —N(R⁴)(R⁵), wherein R⁴ and R⁵ are as described above.

As used here, the term “alkylene” refers to a divalent alkyl group thathas two points of attachment to the rest of the compound. An alkylmoiety of an alkylene group, alone or as a part of a larger moiety(alkoxy, alkylammonium, and the like) is preferably a straight chainedor branched saturated aliphatic group with 1 to about 12 carbon atoms,e.g., methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl,tert-butyl, pentyl, hexyl, heptyl or octyl, or a saturatedcycloaliphatic group with 3 to about 12 carbon atoms. Non-limitingexamples of alkylene groups include a divalent C1-6 groups such asmethylene (—CH₂—), ethylene (—CH₂CH₂—), n-propylene (—CH₂CH₂CH₂—),isopropylene (—CH₂CH(CH₃)—), and the like. Examples of a divalent C1-6alkyl group include, for example, a methylene group, an ethylene group,an ethylidene group, an n-propylene group, an isopropylene group, anisobutylene group, an s-butylene group, an n-butylene group, and at-butylene group.

“Cycloalkyl” means a saturated aliphatic cyclic hydrocarbon radicalhaving the specified number of carbon atoms. (C₃-C₆)cycloalkyl includescyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. The cycloalkyl canbe (3-7 membered) monocyclic, (6-13 membered) fused bicyclic, (4-13membered) bridged bicyclic, (6-13 membered) spiro bicyclic or bridgedtricyclic (e.g., adamantyl). Suitable substituents for a “substitutedcycloalkyl” include, but are not limited to halogen, —OH, —O—C₁-C₄alkyl, C₁-C₄ alkyl, fluoro-substituted-C₁-C₄ alkyl, C₃-C₁₀ carbocyclyl(e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl ornaphthalenyl), a (4-13 membered) heterocyclyl (e.g., pyrrolidine,piperidine, piperazine, tetrahydrofuran, tetrahydropyran or morpholine),or —N(R⁴)(R⁵), wherein R⁴ and R⁵ are as described above.

“Heterocycle” means a saturated or partially unsaturated (4-13 membered)heterocyclic ring containing 1, 2, 3 or 4 heteroatoms independentlyselected from N, O or S, and includes for example heteroaryl. When oneheteroatom is S, it can be optionally mono- or di-oxygenated (i.e.—S(O)— or —S(O)₂—). The heterocycle can be (4-7 membered) monocyclic,(6-13 membered) fused bicyclic, (6-13 membered) bridged bicyclic, or(6-13 membered) spiro bicyclic.

Examples of monocyclic heterocycle include, but not limited to,azetidine, pyrrolidine, piperidine, piperazine, hexahydropyrimidine,tetrahydrofuran, tetrahydropyran, morpholine, thiomorpholine,thiomorpholine 1,1-dioxide, tetrahydro-2H-1,2-thiazine,tetrahydro-2H-1,2-thiazine 1,1-dioxide, isothiazolidine, orisothiazolidine 1,1-dioxide.

A fused bicyclic heterocycle has two rings which have two adjacent ringatoms in common. The first ring is a monocyclic heterocycle and thesecond ring is a cycloalkyl, partially unsaturated carbocycle, phenyl orheteroaryl (e.g., pyrrole, imidazole, pyrazole, oxazole, isoxazole,thiazole, isothiazole, 1,2,3-triazole, 1,2,4-triazole, 1,3,4-oxadiazole,1,2,5-thiadiazole, 1,2,5-thiadiazole 1-oxide, 1,2,5-thiadiazole1,1-dioxide, 1,3,4-thiadiazole, pyridine, pyrazine, pyrimidine,pyridazine, 1,2,4-triazine, 1,3,5-triazine, and tetrazole).

A spiro bicyclic heterocycle has two rings which have only one ring atomin common. The first ring is a monocyclic heterocycle and the secondring is a cycloalkyl, partially unsaturated carbocycle or a monocyclicheterocycle. For example, the second ring is a (C₃-C₆)cycloalkyl.Example of spiro bicyclic heterocycle includes, but not limited to,azaspiro[4.4]nonane, 7-azaspiro[4.4]nonane, azaspiro[4.5]decane,8-azaspiro[4.5]decane, azaspiro[5.5]undecane, 3-azaspiro[5.5]undecaneand 3,9-di azaspiro[5.5]undecane.

A bridged bicyclic heterocycle has two rings which have three or moreadjacent ring atoms in common. The first ring is a monocyclicheterocycle and the other ring is a cycloalkyl (such as(C₃-C₆)cycloalkyl), partially unsaturated carbocycle or a monocyclicheterocycle. Examples of bridged bicyclic heterocycles include, but arenot limited to, azabicyclo[3.3.1]nonane, 3-azabicyclo[3.3.1]nonane,azabicyclo[3.2.1]octane, 3-azabicyclo[3.2.1]octane,6-azabicyclo[3.2.1]octane and azabicyclo[2.2.2]octane,2-azabicyclo[2.2.2]octane.

“Heteroaryl” means a (5-12 membered) monovalent heteroaromaticmonocyclic or bicyclic ring radical. A heteroaryl contains 1, 2, 3 or 4heteroatoms independently selected from N, O, and S. Heteroarylsinclude, but are not limited to pyrrole, imidazole, pyrazole, oxazole,isoxazole, thiazole, isothiazole, 1,2,3-triazole, 1,2,4-triazole,1,3,4-oxadiazole, 1,2,5-thiadiazole, 1,2,5-thiadiazole 1-oxide,1,2,5-thiadiazole 1,1-dioxide, 1,3,4-thiadiazole, pyridine, pyrazine,pyrimidine, pyridazine, 1,2,4-triazine, 1,3,5-triazine, and tetrazole.Bicyclic heteroaryl rings include, but are not limited to,bicyclo[4.4.0] and bicyclo[4.3.0] fused ring systems such as indolizine,indole, isoindole, indazole, benzimidazole, benzthiazole, purine,quinoline, isoquinoline, cinnoline phthalazine, quinazoline,quinoxaline, 1,8-naphthyridine, and pteridine.

“Carbocyclyl” and “carbocycle” both mean (3-10 membered) saturated,partially saturated or unsaturated aliphatic cyclic hydrocarbon ring andincludes for example aryl. “Carbocyclyl” includes, but are not limitedto C₃-C₆ cycloalkyl and aryl. C₃-C₆ cycloalkyl includes, but is notlimited to optionally substituted cyclopropyl, cyclobutyl, cyclopentyland cyclohexyl.

“Aryl” means an aromatic monocyclic or polycyclic (e.g. bicyclic ortricyclic) carbocyclic ring system. Aryl systems include, but notlimited to, phenyl, naphthalenyl, fluorenyl, indenyl, azulenyl, andanthracenyl.

“Alkoxy” means an alkyl radical attached through an oxygen linking atom.“(C₁-C₄)-alkoxy” includes methoxy, ethoxy, propoxy, and butoxy.

“Alkylthio” means an alkyl radical attached through a sulfur linkingatom. “(C₁-C₄)alkylthio” include methylthio, ethylthio, propylthio andbutylthio.

“Alkylsulfinyl” means an alkyl radical attached through a —S(O)— linkinggroup. “(C₁-C₄)alkylsulfinyl” include methylsulfinyl, ethylsulfinyl,propylsulfinyl and butylsulfinyl.

“Alkylsulfonyl” means an alkyl radical attached through a —S(O)₂—linking group. “(C₁-C₄)alkylsulfonyl” include methyl sulfonyl,ethylsulfonyl, propyl sulfonyl and butylsulfonyl.

Haloalkyl and halocycloalkyl include mono, poly, and perhaloalkyl groupswhere each halogen is independently selected from fluorine, chlorine,and bromine.

“Cycloalkoxy” means a cycloalkyl radical attached through an oxygenlinking atom. “(C₃-C₆)cycloalkoxy” includes cyclopropyloxy,cyclobutyloxy, cyclopentyloxy and cyclohexyloxy.

“Aryloxy” means an aryl moiety attached through an oxygen linking atom.Aryloxy includes, but not limited to, phenoxy.

“Arylthio” means an aryl moiety attached through a sulfur linking atom.Arylthio includes, but not limited to, phenylthio.

“Arylsulfinyl” means an aryl moiety attached through a —S(O)— linkinggroup. Arylsulfinyl includes, but not limited to, phenylsulfinyl.

“Arylsulfonyl” means an aryl moiety attached through a —S(O)₂— linkinggroup. Arylsulfonyl includes, but not limited to, phenylsulfonyl.

“Hetero” refers to the replacement of at least one carbon atom member ina ring system with at least one heteroatom selected from N, S, and O. Ahetero ring system may have 1, 2, or 3 carbon atom members replaced by aheteroatom.

“Halogen” and “halo” are interchangeably used herein and each refers tofluorine, chlorine, bromine, or iodine.

Another embodiment of the present invention is a pharmaceuticalcomposition comprising one or more pharmaceutically acceptable carrierand/or diluent and a compound disclosed herein or a pharmaceuticallyacceptable salt thereof.

“Pharmaceutically acceptable carrier” means non-therapeutic componentsthat are of sufficient purity and quality for use in the formulation ofa composition of the invention that, when appropriately administered toan animal or human, typically do not produce an adverse reaction, andthat are used as a vehicle for a drug substance (i.e. a compound of thepresent invention).

“Pharmaceutically acceptable diluent” means non-therapeutic componentsthat are of sufficient purity and quality for use in the formulation ofa composition of the invention that, when appropriately administered toan animal or human, typically do not produce an adverse reaction, andthat are used as a diluting agent for a drug substance (i.e. a compoundof the present invention).

Pharmaceutically acceptable salts of the compounds of the presentinvention are also included. For example, an acid salt of a compound ofthe present invention containing an amine or other basic group can beobtained by reacting the compound with a suitable organic or inorganicacid, resulting in pharmaceutically acceptable anionic salt forms.Examples of anionic salts include the acetate, benzenesulfonate,benzoate, bicarbonate, bitartrate, bromide, calcium edetate, camsylate,carbonate, chloride, citrate, dihydrochloride, edetate, edisylate,estolate, esylate, fumarate, glyceptate, gluconate, glutamate,glycollylarsanilate, hexylresorcinate, hydrobromide, hydrochloride,hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, malate,maleate, mandelate, mesylate, methylsulfate, mucate, napsylate, nitrate,pamoate, pantothenate, phosphate/diphosphate, polygalacturonate,salicylate, stearate, subacetate, succinate, sulfate, tannate, tartrate,teoclate, tosylate, and triethiodide salts.

Salts of the compounds of the present invention containing a carboxylicacid or other acidic functional group can be prepared by reacting with asuitable base. Such a pharmaceutically acceptable salt may be made witha base which affords a pharmaceutically acceptable cation, whichincludes alkali metal salts (especially sodium and potassium), alkalineearth metal salts (especially calcium and magnesium), aluminum salts andammonium salts, as well as salts made from physiologically acceptableorganic bases such as trimethylamine, triethylamine, morpholine,pyridine, piperidine, picoline, dicyclohexylamine,N,N′-dibenzylethylenediamine, 2-hydroxyethylamine,bis-(2-hydroxyethyl)amine, tri-(2-hydroxyethyl)amine, procaine,dibenzylpiperidine, dehydroabietylamine, N,N′-bisdehydroabietylamine,glucamine, N-methylglucamine, collidine, quinine, quinoline, and basicamino acids such as lysine and arginine.

The invention also includes various isomers and mixtures thereof.Certain of the compounds of the present invention may exist in variousstereoisomeric forms. Stereoisomers are compounds which differ only intheir spatial arrangement. Enantiomers are pairs of stereoisomers whosemirror images are not superimposable, most commonly because they containan asymmetrically substituted carbon atom that acts as a chiral center.“Enantiomer” means one of a pair of molecules that are mirror images ofeach other and are not superimposable. Diastereomers are stereoisomersthat are not related as mirror images, most commonly because theycontain two or more asymmetrically substituted carbon atoms. “R” and “S”represent the configuration of substituents around one or more chiralcarbon atoms. When a chiral center is not defined as R or S, a mixtureof both configurations is present.

“Racemate” or “racemic mixture” means a compound of equimolar quantitiesof two enantiomers, wherein such mixtures exhibit no optical activity;i.e., they do not rotate the plane of polarized light.

The compounds of the invention may be prepared as individual isomers byeither isomer-specific synthesis or resolved from an isomeric mixture.Conventional resolution techniques include forming the salt of a freebase of each isomer of an isomeric pair using an optically active acid(followed by fractional crystallization and regeneration of the freebase), forming the salt of the acid form of each isomer of an isomericpair using an optically active amine (followed by fractionalcrystallization and regeneration of the free acid), forming an ester oramide of each of the isomers of an isomeric pair using an optically pureacid, amine or alcohol (followed by chromatographic separation andremoval of the chiral auxiliary), or resolving an isomeric mixture ofeither a starting material or a final product using various well knownchromatographic methods.

When the stereochemistry of a disclosed compound is named or depicted bystructure, the named or depicted stereoisomer is at least 60%, 70%, 80%,90%, 99% or 99.9% by weight pure relative to the other stereoisomers.When a single enantiomer is named or depicted by structure, the depictedor named enantiomer is at least 60%, 70%, 80%, 90%, 99% or 99.9% byweight optically pure. Percent optical purity by weight is the ratio ofthe weight of the enantiomer over the weight of the enantiomer plus theweight of its optical isomer.

The present invention also provides a method of treating a subject witha tetracycline-responsive disease or disorder comprising administeringto the subject an effective amount of a compound of the presentinvention or a pharmaceutically acceptable salt thereof.

“Tetracycline-responsive disease or disorder” refers to a disease ordisorder that can be treated, prevented, or otherwise ameliorated by theadministration of a tetracycline compound of the present invention.Tetracycline-responsive disease or disorder includes infections, cancer,inflammatory disorders, autoimmune disease, arteriosclerosis, cornealulceration, emphysema, arthritis, osteoporosis, osteoarthritis, multiplesclerosis, osteosarcoma, osteomyelitis, bronchiectasis, chronicpulmonary obstructive disease, skin and eye diseases, periodontitis,osteoporosis, rheumatoid arthritis, ulcerative colitis, inflammatorydisorders, tumor growth and invasion, metastasis, acute lung injury,stroke, ischemia, diabetes, aortic or vascular aneurysms, skin tissuewounds, dry eye, bone, cartilage degradation, malaria, senescence,diabetes, vascular stroke, neurodegenerative disorders, cardiac disease,juvenile diabetes, acute and chronic bronchitis, sinusitis, andrespiratory infections, including the common cold; acute and chronicgastroenteritis and colitis; acute and chronic cystitis and urethritis;acute and chronic dermatitis; acute and chronic conjunctivitis; acuteand chronic serositis; uremic pericarditis; acute and chroniccholecystis; cystic fibrosis, acute and chronic vaginitis; acute andchronic uveitis; drug reactions; insect bites; burns and sunburn, bonemass disorder, acute lung injury, chronic lung disorders, ischemia,stroke or ischemic stroke, skin wound, aortic or vascular aneurysm,diabetic retinopathy, hemorrhagic stroke, angiogenesis, and other statesfor which tetracycline compounds have been found to be active (see, forexample, U.S. Pat. Nos. 5,789,395; 5,834,450; 6,277,061 and 5,532,227,each of which is expressly incorporated herein by reference). Compoundsof the invention can be used to prevent or control important mammalianand veterinary diseases such as diarrhea, urinary tract infections,infections of skin and skin structure, ear, nose and throat infections,wound infection, mastitis and the like. In addition, methods fortreating neoplasms using tetracycline compounds of the invention arealso included (van der Bozert et al., Cancer Res., 48: 6686-6690(1988)).

Infections that can be treated using compounds of the invention (i.e.compound of Structural Formula (I)) or a pharmaceutically acceptablesalt thereof include, but are not limited to, skin infections, GIinfections, urinary tract infections, genito-urinary infections,respiratory tract infections, sinuses infections, middle ear infections,systemic infections, cholera, influenza, bronchitis, acne, malaria,sexually transmitted disease including syphilis and gonorrhea,Legionnaires' disease, Lyme disease, Rocky Mountain spotted fever, Qfever, typhus, bubonic plague, gas gangrene, hospital acquiredinfections, leptospirosis, whooping cough, anthrax and infections causedby the agents responsible for lymphogranuloma venereum, inclusionconjunctivitis, or psittacosis. Infections can be bacterial, fungal,parasitic and viral infections (including those which are resistant toother tetracycline compounds).

In one embodiment, the infection can be caused bacteria. In anotherembodiment, the infection is caused by a Gram-positive bacteria. In aspecific aspect of this embodiment, the infection is caused by aGram-positive bacteria selected from S. aureus, S.pneumoniae, P.granulosum and P. acnes.

In another embodiment, the infection is caused by a Gram-negativebacteria. In a specific aspect of this embodiment, the infection iscaused by a Gram-negative bacteria selected from E. coli or B.thetaiotaomicron.

In another embodiment, the infection is caused by an organism selectedfrom the group consisting of K. pneumoniae, Salmonella, E. hirae, A.baumanii, B. catarrhalis, H. influenzae, P. aeruginosa, E. faecium, E.coli, S. aureus, and E. faecalis. In another embodiment, the infectionis caused by an organism selected from the group consisting ofrickettsiae, chlamydiae, and Mycoplasma pneumoiae. In anotherembodiment, the infection is caused by an organism resistant totetracycline. In another embodiment, the infection is caused by anorganism resistant to methicillin. In another embodiment, the infectionis caused by an organism resistant to vancomycin. In another embodimentthe infection is a Bacillus anthracis infection. “Bacillus anthracisinfection” includes any state, diseases, or disorders caused or whichresult from exposure or alleged exposure to Bacillus anthracis oranother member of the Bacillus cereus group of bacteria.

In a further embodiment, the tetracycline responsive disease or disorderis not a bacterial infection. In another embodiment, the tetracyclinecompounds of the invention are essentially non-antibacterial. Forexample, non-antibacterial compounds of the invention may have MICvalues greater than about 4 μg/ml (as measured by assays known in theart and/or the assay given in Example 22).

Tetracycline responsive disease or disorder also includes diseases ordisorders associated with inflammatory process associated states (IPAS).The term “inflammatory process associated state” includes states inwhich inflammation or inflammatory factors (e.g., matrixmetalloproteinases (MMPs), nitric oxide (NO), TNF, interleukins, plasmaproteins, cellular defense systems, cytokines, lipid metabolites,proteases, toxic radicals, adhesion molecules, etc.) are involved or arepresent in an area in aberrant amounts, e.g., in amounts which may beadvantageous to alter, e.g., to benefit the subject. The inflammatoryprocess is the response of living tissue to damage. The cause ofinflammation may be due to physical damage, chemical substances,micro-organisms, tissue necrosis, cancer or other agents. Acuteinflammation is short-lasting, lasting only a few days. If it is longerlasting however, then it may be referred to as chronic inflammation.

IPASs include inflammatory disorders. Inflammatory disorders aregenerally characterized by heat, redness, swelling, pain and loss offunction. Examples of causes of inflammatory disorders include, but arenot limited to, microbial infections (e.g., bacterial and fungalinfections), physical agents (e.g., burns, radiation, and trauma),chemical agents (e.g., toxins and caustic substances), tissue necrosisand various types of immunologic reactions.

Examples of inflammatory disorders can be treated using the compounds ofthe invention (i.e. compound of Structural Formula (I)) or apharmaceutically acceptable salt thereof include, but are not limitedto, osteoarthritis, rheumatoid arthritis, acute and chronic infections(bacterial and fungal, including diphtheria and pertussis); acute andchronic bronchitis, sinusitis, and upper respiratory infections,including the common cold; acute and chronic gastroenteritis andcolitis; inflammatory bowel disorder; acute and chronic cystitis andurethritis; vasculitis; sepsis; nephritis; pancreatitis; hepatitis;lupus; inflammatory skin disorders including, for example, eczema,dermatitis, psoriasis, pyoderma gangrenosum, acne rosacea, and acute andchronic dermatitis; acute and chronic conjunctivitis; acute and chronicserositis (pericarditis, peritonitis, synovitis, pleuritis andtendinitis); uremic pericarditis; acute and chronic cholecystis; acuteand chronic vaginitis; acute and chronic uveitis; drug reactions; insectbites; burns (thermal, chemical, and electrical); and sunburn

IPASs also include matrix metalloproteinase associated states (MMPAS).MMPAS include states characterized by aberrant amounts of MMPs or MMPactivity. Examples of matrix metalloproteinase associated states(“MMPAS's”) can be treated using compounds of the invention or apharmaceutically acceptable salt thereof, include, but are not limitedto, arteriosclerosis, corneal ulceration, emphysema, osteoarthritis,multiple sclerosis (Liedtke et al., Ann. Neurol. 1998, 44: 35-46;Chandler et al., J. Neuroimmunol. 1997, 72: 155-71), osteosarcoma,osteom/zyelitis, bronchiectasis, chronic pulmonary obstructive disease,skin and eye diseases, periodontitis, osteoporosis, rheumatoidarthritis, ulcerative colitis, inflammatory disorders, tumor growth andinvasion (Stetler-Stevenson et al., Annu. Rev. Cell Biol. 1993, 9:541-73; Tryggvason et al., Biochim. Biophys. Acta 1987, 907: 191-217; Liet al., Mol. Carcillog 1998, 22: 84-89)), metastasis, acute lung injury,stroke, ischemia, diabetes, aortic or vascular aneurysms, skin tissuewounds, dry eye, bone and cartilage degradation (Greenwald et al., Bone1998, 22: 33-38; Ryan et al., Curr. Op. Rheumatol. 1996, 8: 238-247).Other MMPAS include those described in U.S. Pat. Nos. 5,459,135;5,321,017; 5,308,839; 5,258,371; 4,935,412; 4,704,383, 4,666,897, and RE34,656, incorporated herein by reference in their entirety.

In a further embodiment, the IPAS includes disorders described in U.S.Pat. Nos. 5,929,055; and 5,532,227, incorporated herein by reference intheir entirety.

Tetracycline responsive disease or disorder also includes diseases ordisorders associated with NO associated states. The term “NO associatedstates” includes states which involve or are associated with nitricoxide (NO) or inducible nitric oxide synthase (iNOS). NO associatedstate includes states which are characterized by aberrant amounts of NOand/or iNOS. Preferably, the NO associated state can be treated byadministering tetracycline compounds of the invention. The disorders,diseases and states described in U.S. Pat. Nos. 6,231,894; 6,015,804;5,919,774; and 5,789,395 are also included as NO associated states. Theentire contents of each of these patents are hereby incorporated hereinby reference.

Examples of diseases or disorders associated with NO associated statescan be treated using the compounds of the present invention (i.e.compound of Structural Formula (I)) or a pharmaceutically acceptablesalt thereof include, but are not limited to, malaria, senescence,diabetes, vascular stroke, neurodegenerative disorders (Alzheimer'sdisease and Huntington's disease), cardiac disease(reperfusion-associated injury following infarction), juvenile diabetes,inflammatory disorders, osteoarthritis, rheumatoid arthritis, acute,recurrent and chronic infections (bacterial, viral and fungal); acuteand chronic bronchitis, sinusitis, and respiratory infections, includingthe common cold; acute and chronic gastroenteritis and colitis; acuteand chronic cystitis and urethritis; acute and chronic dermatitis; acuteand chronic conjunctivitis; acute and chronic serositis (pericarditis,peritonitis, synovitis, pleuritis and tendonitis); uremic pericarditis;acute and chronic cholecystis; cystic fibrosis, acute and chronicvaginitis; acute and chronic uveitis; drug reactions; insect bites;burns (thermal, chemical, and electrical); and sunburn.

In another embodiment, the tetracycline responsive disease or disorderis cancer. Examples of cancers that can be treated using the compoundsof the invention (i.e. compound of Structural Formula (I)) or apharmaceutically acceptable salt thereof include all solid tumors, i.e.,carcinomas e.g., adenocarcinomas, and sarcomas. Adenocarcinomas arecarcinomas derived from glandular tissue or in which the tumor cellsform recognizable glandular structures. Sarcomas broadly include tumorswhose cells are embedded in a fibrillar or homogeneous substance likeembryonic connective tissue. Examples of carcinomas which may be treatedusing the methods of the invention include, but are not limited to,carcinomas of the prostate, breast, ovary, testis, lung, colon, andbreast. The methods of the invention are not limited to the treatment ofthese tumor types, but extend to any solid tumor derived from any organsystem. Examples of treatable cancers include, but are not limited to,colon cancer, bladder cancer, breast cancer, melanoma, ovariancarcinoma, prostate carcinoma, lung cancer, and a variety of othercancers as well. The methods of the invention also cause the inhibitionof cancer growth in adenocarcinomas, such as, for example, those of theprostate, breast, kidney, ovary, testes, and colon. In one embodiment,the cancers treated by methods of the invention include those describedin U.S. Pat. Nos. 6,100,248; 5,843,925; 5,837,696; or 5,668,122,incorporated herein by reference in their entirety.

Alternatively, the tetracycline compounds may be useful for preventingor reducing the likelihood of cancer recurrence, for example, to treatresidual cancer following surgical resection or radiation therapy. Thetetracycline compounds useful according to the invention are especiallyadvantageous as they are substantially non-toxic compared to othercancer treatments.

In a further embodiment, the compounds of the invention are administeredin combination with standard cancer therapy, such as, but not limitedto, chemotherapy.

Examples of tetracycline responsive states can be treated using thecompounds of the invention (i.e. compound of Structural Formula (I)) ora pharmaceutically acceptable salt thereof also include neurologicaldisorders which include both neuropsychiatric and neurodegenerativedisorders, but are not limited to, such as Alzheimer's disease,dementias related to Alzheimer's disease (such as Pick's disease),Parkinson's and other Lewy diffuse body diseases, senile dementia,Huntington's disease, Gilles de la Tourette's syndrome, multiplesclerosis, amyotrophic lateral sclerosis (ALS), progressive supranuclearpalsy, epilepsy, and Creutzfeldt-Jakob disease; autonomic functiondisorders such as hypertension and sleep disorders, and neuropsychiatricdisorders, such as depression, schizophrenia, schizoaffective disorder,Korsakoffs psychosis, mania, anxiety disorders, or phobic disorders;learning or memory disorders, e.g., amnesia or age-related memory loss,attention deficit disorder, dysthymic disorder, major depressivedisorder, mania, obsessive-compulsive disorder, psychoactive substanceuse disorders, anxiety, phobias, panic disorder, as well as bipolaraffective disorder, e.g., severe bipolar affective (mood) disorder(BP-1), bipolar affective neurological disorders, e.g., migraine andobesity.

Further neurological disorders include, for example, those listed in theAmerican Psychiatric Association's Diagnostic and Statistical manual ofMental Disorders (DSM), the most current version of which isincorporated herein by reference in its entirety.

In another embodiment, the tetracycline responsive disease or disorderis diabetes. Diabetes that can be treated using the compounds of theinvention or a pharmaceutically acceptable salt thereof include, but arenot limited to, juvenile diabetes, diabetes mellitus, diabetes type I,or diabetes type II. In a further embodiment, protein glycosylation isnot affected by the administration of the tetracycline compounds of theinvention. In another embodiment, the tetracycline compound of theinvention is administered in combination with standard diabetictherapies, such as, but not limited to insulin therapy.

In another embodiment, the tetracycline responsive disease or disorderis a bone mass disorder. Bone mass disorders that can be treated usingthe compounds of the invention or a pharmaceutically acceptable saltthereof include disorders where a subjects bones are disorders andstates where the formation, repair or remodeling of bone isadvantageous. For examples bone mass disorders include osteoporosis(e.g., a decrease in bone strength and density), bone fractures, boneformation associated with surgical procedures (e.g., facialreconstruction), osteogenesis imperfecta (brittle bone disease),hypophosphatasia, Paget's disease, fibrous dysplasia, osteopetrosis,myeloma bone disease, and the depletion of calcium in bone, such as thatwhich is related to primary hyperparathyroidism. Bone mass disordersinclude all states in which the formation, repair or remodeling of boneis advantageous to the subject as well as all other disorders associatedwith the bones or skeletal system of a subject which can be treated withthe tetracycline compounds of the invention. In a further embodiment,the bone mass disorders include those described in U.S. Pat. Nos.5,459,135; 5,231,017; 5,998,390; 5,770,588; RE 34,656; 5,308,839;4,925,833; 3,304,227; and 4,666,897, each of which is herebyincorporated herein by reference in its entirety.

In another embodiment, the tetracycline responsive disease or disorderis acute lung injury. Acute lung injuries that can be treated using thecompounds of the invention or a pharmaceutically acceptable salt thereofinclude adult respiratory distress syndrome (ARDS), post-pump syndrome(PPS), and trauma. Trauma includes any injury to living tissue caused byan extrinsic agent or event. Examples of trauma include, but are notlimited to, crush injuries, contact with a hard surface, or cutting orother damage to the lungs.

The tetracycline responsive disease or disorder of the invention alsoincludes chronic lung disorders. Examples of chronic lung disorders thatcan be treated using the compounds of the invention or apharmaceutically acceptable salt thereof include, but are not limited,to asthma, cystic fibrosis, chronic obstructive pulmonary disease(COPD), and emphysema. In a further embodiment, the acute and/or chroniclung disorders that can be treated using the compounds of the inventionor a pharmaceutically acceptable salt thereof include those described inU.S. Pat. Nos. 5,977,091; 6,043,231; 5,523,297; and 5,773,430, each ofwhich is hereby incorporated herein by reference in its entirety.

In yet another embodiment, the tetracycline responsive disease ordisorder is ischemia, stroke, or ischemic stroke.

In a further embodiment, the tetracycline compounds of the invention ora pharmaceutically acceptable salt thereof can be used to treat suchdisorders as described above and in U.S. Pat. Nos. 6,231,894; 5,773,430;5,919,775 and 5,789,395, incorporated herein by reference.

In another embodiment, the tetracycline responsive disease or disorderis a skin wound. The invention also provides a method for improving thehealing response of the epithelialized tissue (e.g., skin, mucosae) toacute traumatic injury (e.g., cut, burn, scrape, etc.). The methodincludes using a tetracycline compound of the invention or apharmaceutically acceptable salt thereof to improve the capacity of theepithelialized tissue to heal acute wounds. The method may increase therate of collagen accumulation of the healing tissue. The method may alsodecrease the proteolytic activity in the epithelialized tissue bydecreasing the collagenolytic and/or gellatinolytic activity of MMPs. Ina further embodiment, the tetracycline compound of the invention or apharmaceutically acceptable salt thereof is administered to the surfaceof the skin (e.g., topically). In a further embodiment, the tetracyclinecompound of the invention or a pharmaceutically acceptable salt thereofis used to treat a skin wound, and other such disorders as described in,for example, U.S. Pat. Nos. 5,827,840; 4,704,383; 4,935,412; 5,258,371;5,308,839, 5,459,135; 5,532,227; and 6,015,804; each of which isincorporated herein by reference in its entirety.

In yet another embodiment, the tetracycline responsive disease ordisorder is an aortic or vascular aneurysm in vascular tissue of asubject (e.g., a subject having or at risk of having an aortic orvascular aneurysm, etc.). The tetracycline compound or apharmaceutically acceptable salt thereof may be effective to reduce thesize of the vascular aneurysm or it may be administered to the subjectprior to the onset of the vascular aneurysm such that the aneurysm isprevented. In one embodiment, the vascular tissue is an artery, e.g.,the aorta, e.g., the abdominal aorta. In a further embodiment, thetetracycline compounds of the invention are used to treat disordersdescribed in U.S. Pat. Nos. 6,043,225 and 5,834,449, incorporated hereinby reference in their entirety.

The compounds of the invention or a pharmaceutically acceptable saltthereof can be used alone or in combination with one or more therapeuticagent in the methods of the invention disclosed herein.

The language “in combination with” another therapeutic agent ortreatment includes co-administration of the tetracycline compound andwith the other therapeutic agent or treatment as either a singlecombination dosage form or as multiple, separate dosage forms,administration of the tetracycline compound first, followed by the othertherapeutic agent or treatment and administration of the othertherapeutic agent or treatment first, followed by the tetracyclinecompound.

The other therapeutic agent may be any agent that is known in the art totreat, prevent, or reduce the symptoms of a tetracycline-responsivedisease or disorder. The choice of additional therapeutic agent(s) isbased upon the particular tetracycline-responsive disease or disorderbeing treated. Such choice is within the knowledge of a treatingphysician. Furthermore, the other therapeutic agent may be any agent ofbenefit to the patient when administered in combination with theadministration of a tetracycline compound.

As used herein, the term “subject” means a mammal in need of treatment,e.g., companion animals (e.g., dogs, cats, and the like), farm animals(e.g., cows, pigs, horses, sheep, goats and the like) and laboratoryanimals (e.g., rats, mice, guinea pigs and the like). Typically, thesubject is a human in need of the specified treatment.

As used herein, the term “treating” or “treatment” refers to obtainingdesired pharmacological and/or physiological effect. The effect can beprophylactic or therapeutic, which includes achieving, partially orsubstantially, one or more of the following results: partially ortotally reducing the extent of the disease, disorder or syndrome;ameliorating or improving a clinical symptom or indicator associatedwith the disorder; delaying, inhibiting or decreasing the likelihood ofthe progression of the disease, disorder or syndrome; or partially ortotally delaying, inhibiting or reducing the likelihood of the onset ordevelopment of disease, disorder or syndrome.

“Effective amount” means that amount of active compound agent thatelicits the desired biological response in a subject. Such responseincludes alleviation of the symptoms of the disease or disorder beingtreated. In one embodiment, the effective amount of a compound of theinvention is from about 0.01 mg/kg/day to about 1000 mg/kg/day, fromabout 0.1 mg/kg/day to about 100 mg/kg/day, or from about 0.5 mg/kg/dayto about 50 mg/kg/day.

The invention further includes the process for making the compositioncomprising mixing one or more of the present compounds and an optionalpharmaceutically acceptable carrier; and includes those compositionsresulting from such a process, which process includes conventionalpharmaceutical techniques.

The compositions of the invention include ocular, oral, nasal,transdermal, topical with or without occlusion, intravenous (both bolusand infusion), and injection (intraperitoneally, subcutaneously,intramuscularly, intratumorally, or parenterally). The composition maybe in a dosage unit such as a tablet, pill, capsule, powder, granule,liposome, ion exchange resin, sterile ocular solution, or oculardelivery device (such as a contact lens and the like facilitatingimmediate release, timed release, or sustained release), parenteralsolution or suspension, metered aerosol or liquid spray, drop, ampoule,auto-injector device, or suppository; for administration ocularly,orally, intranasally, sublingually, parenterally, or rectally, or byinhalation or insufflation.

Compositions of the invention suitable for oral administration includesolid forms such as pills, tablets, caplets, capsules (each includingimmediate release, timed release, and sustained release formulations),granules and powders; and, liquid forms such as solutions, syrups,elixirs, emulsions, and suspensions. Forms useful for ocularadministration include sterile solutions or ocular delivery devices.Forms useful for parenteral administration include sterile solutions,emulsions, and suspensions.

The compositions of the invention may be administered in a form suitablefor once-weekly or once-monthly administration. For example, aninsoluble salt of the active compound may be adapted to provide a depotpreparation for intramuscular injection (e.g., a decanoate salt) or toprovide a solution for ophthalmic administration.

The dosage form containing the composition of the invention contains aneffective amount of the active ingredient necessary to provide atherapeutic effect. The composition may contain from about 5,000 mg toabout 0.5 mg (preferably, from about 1,000 mg to about 0.5 mg) of acompound of the invention or salt form thereof and may be constitutedinto any form suitable for the selected mode of administration. Thecomposition may be administered about 1 to about 5 times per day. Dailyadministration or post-periodic dosing may be employed.

For oral administration, the composition is preferably in the form of atablet or capsule containing, e.g., 500) to 0.5 milligrams of the activecompound. Dosages will vary depending on factors associated with theparticular patient being treated (e.g., age, weight, diet, and time ofadministration), the severity of the condition being treated, thecompound being employed, the mode of administration, and the strength ofthe preparation.

The oral composition is preferably formulated as a homogeneouscomposition, wherein the active ingredient is dispersed evenlythroughout the mixture, which may be readily subdivided into dosageunits containing equal amounts of a compound of the invention.Preferably, the compositions are prepared by mixing a compound of theinvention (or pharmaceutically acceptable salt thereof) with one or moreoptionally present pharmaceutical carriers (such as a starch, sugar,diluent, granulating agent, lubricant, glidant, binding agent, anddisintegrating agent), one or more optionally present inertpharmaceutical excipients (such as water, glycols, oils, alcohols,flavoring agents, preservatives, coloring agents, and syrup), one ormore optionally present conventional tableting ingredients (such as cornstarch, lactose, sucrose, sorbitol, talc, stearic acid, magnesiumstearate, dicalcium phosphate, and any of a variety of gums), and anoptional diluent (such as water).

Binder agents include starch, gelatin, natural sugars (e.g., glucose andbeta-lactose), corn sweeteners and natural and synthetic gums (e.g.,acacia and tragacanth). Disintegrating agents include starch, methylcellulose, agar, and bentonite.

Tablets and capsules represent an advantageous oral dosage unit form.Tablets may be sugarcoated or filmcoated using standard techniques.Tablets may also be coated or otherwise compounded to provide aprolonged, control-release therapeutic effect. The dosage form maycomprise an inner dosage and an outer dosage component, wherein theouter component is in the form of an envelope over the inner component.The two components may further be separated by a layer which resistsdisintegration in the stomach (such as an enteric layer) and permits theinner component to pass intact into the duodenum or a layer which delaysor sustains release. A variety of enteric and non-enteric layer orcoating materials (such as polymeric acids, shellacs, acetyl alcohol,and cellulose acetate or combinations thereof) may be used.

Compounds of the invention may also be administered via a slow releasecomposition; wherein the composition includes a compound of theinvention and a biodegradable slow release carrier (e.g., a polymericcarrier) or a pharmaceutically acceptable non-biodegradable slow releasecarrier (e.g., an ion exchange carrier).

Biodegradable and non-biodegradable slow release carriers are well knownin the art. Biodegradable carriers are used to form particles ormatrices which retain an active agent(s) and which slowlydegrade/dissolve in a suitable environment (e.g., aqueous, acidic, basicand the like) to release the agent. Such particles degrade/dissolve inbody fluids to release the active compound(s) therein. The particles arepreferably nanoparticles (e.g., in the range of about 1 to 500 nm indiameter, preferably about 50-200 nm in diameter, and most preferablyabout 100 nm in diameter). In a process for preparing a slow releasecomposition, a slow release carrier and a compound of the invention arefirst dissolved or dispersed in an organic solvent. The resultingmixture is added into an aqueous solution containing an optionalsurface-active agent(s) to produce an emulsion. The organic solvent isthen evaporated from the emulsion to provide a colloidal suspension ofparticles containing the slow release carrier and the compound of theinvention.

The compound disclosed herein may be incorporated for administrationorally or by injection in a liquid form such as aqueous solutions,suitably flavored syrups, aqueous or oil suspensions, flavored emulsionswith edible oils such as cottonseed oil, sesame oil, coconut oil orpeanut oil and the like, or in elixirs or similar pharmaceuticalvehicles. Suitable dispersing or suspending agents for aqueoussuspensions, include synthetic and natural gums such as tragacanth,acacia, alginate, dextran, sodium carboxymethylcellulose,methylcellulose, polyvinyl-pyrrolidone, and gelatin. The liquid forms insuitably flavored suspending or dispersing agents may also includesynthetic and natural gums. For parenteral administration, sterilesuspensions and solutions are desired. Isotonic preparations, whichgenerally contain suitable preservatives, are employed when intravenousadministration is desired.

The compounds may be administered parenterally via injection. Aparenteral formulation may consist of the active ingredient dissolved inor mixed with an appropriate inert liquid carrier. Acceptable liquidcarriers usually comprise aqueous solvents and other optionalingredients for aiding solubility or preservation. Such aqueous solventsinclude sterile water, Ringer's solution, or an isotonic aqueous salinesolution. Other optional ingredients include vegetable oils (such aspeanut oil, cottonseed oil, and sesame oil), and organic solvents (suchas solketal, glycerol, and formyl). A sterile, non-volatile oil may beemployed as a solvent or suspending agent. The parenteral formulation isprepared by dissolving or suspending the active ingredient in the liquidcarrier whereby the final dosage unit contains from 0.005 to 10% byweight of the active ingredient. Other additives include preservatives,isotonizers, solubilizers, stabilizers, and pain-soothing agents.Injectable suspensions may also be prepared, in which case appropriateliquid carriers, suspending agents and the like may be employed.

Compounds of the invention may be administered intranasally using asuitable intranasal vehicle.

Compounds of the invention may also be administered topically using asuitable topical transdermal vehicle or a transdermal patch.

For ocular administration, the composition is preferably in the form ofan ophthalmic composition. The ophthalmic compositions are preferablyformulated as eye-drop formulations and filled in appropriate containersto facilitate administration to the eye, for example a dropper fittedwith a suitable pipette. Preferably, the compositions are sterile andaqueous based, using purified water. In addition to the compound of theinvention, an ophthalmic composition may contain one or more of: a) asurfactant such as a polyoxyethylene fatty acid ester; b) a thickeningagents such as cellulose, cellulose derivatives, carboxyvinyl polymers,polyvinyl polymers, and polyvinylpyrrolidones, typically at aconcentration n the range of about 0.05 to about 5.0% (wt/vol); c) (asan alternative to or in addition to storing the composition in acontainer containing nitrogen and optionally including a free oxygenabsorber such as Fe), an anti-oxidant such as butylated hydroxyanisol,ascorbic acid, sodium thiosulfate, or butylated hydroxytoluene at aconcentration of about 0.00005 to about 0.1% (wt/vol); d) ethanol at aconcentration of about 0.01 to 0.5% (wt/vol); and e) other excipientssuch as an isotonic agent, buffer, preservative, and/or pH-controllingagent. The pH of the ophthalmic composition is desirably within therange of 4 to 8.

In certain embodiments, the composition of this invention includes oneor more additional agents. The other therapeutic agent may be ay agentthat is capable of treating, preventing or reducing the symptoms of atetracycline-responsive disease or disorder. Alternatively, the othertherapeutic agent may be any agent of benefit to a patient whenadministered in combination with the tetracycline compound in thisinvention.

The following abbreviations are used in the synthesis examples below.

Abbreviations

Ac acetylAIBIN 2,2′-azobis(2-methylpropionitrile)aq aqueousBn benzylBoc tert-butoxycarbonylBu butylCbz benzyl oxycarbonylCy tricyclohexylphosphinedba dibenzylideneacetoneDIBAL-H diisobutylaluminum hydride

DIEA N,N-diisopropylethylamine

DMAP 4-(dimethylamino)pyridineDME 1,2-dimethoxyethane

DMF N,N-dimethylformamide

DMPU 1,3-dimethyl-3,4-5,6-tetrahydro-2(1H)-pyrimidoneDMSO dimethyl sulfoxideEDC N-(3-dimethylaminopropyl)-N′-ethylcarbodiimideESI electrospray ionizationEt ethylEtOAc ethyl acetateHPLC high performance liquid chromatographyHOBt 1-hydroxybenzotriazolei isoIBX 2-iodoxybenzoic acidLDA lithium diisopropylamideLHMDS lithium bis(trimethylsilyl)amideLTMP lithium 2,2,6,6-tetramethylpiperidideMeOH methanolMs methanesulfonylMS mass spectrometryMTBE methyl tert-butyl ether

NBS N-bromosuccinimide NCS N-chlorosuccimide

NMR nuclear magnetic resonance spectrometryPh phenylPr propyls secondaryt tertiaryTMEDA N,N,N′N′-tetramethylethylenediamineTBS tert-butyldimethyl silylTEA tri ethylamineTf trifluoromethanesulfonylTFA trifluoroacetic acidTFAA trifluoroacetic anhydrideTHF tetrahydrofuranTLC thin layer chromatographyTs para-toluenesulfonylTsOH para-toluenesulfonic acidXantphos 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene

Example 1 Synthesis of Compounds Via Scheme 1

The following compounds were prepared according to Scheme 1.

To a THF solution of 5-fluoro-2-methoxybenzoic acid (S1-1, 0.50 g, 2.94mmol, 1.0 equiv, Aldrich 523097) cooled at −78° C. was added a THFsolution of s-BuLi (4.60 mL, 1.40 M/cyclohexane, 6.44 mmol, 2.2 equiv)and TMEDA (0.97 mL, 6.47 mmol, 2.2 equiv). The reaction was stirred at−78° C. for 2 hrs. Iodomethane (1.10 mL, 17.64 mmol, 6.0 equiv) wasadded to the reaction mixture dropwise. The reaction was allowed to warmto 25° C. over 1 h and stirred at 25° C. for 1 h. Aqueous NaOH (6 N, 20mL) was added. The resulting mixture was extracted with t-butylmethylether (20 mL×2). The aqueous layer was acidified with hydrochloric acid(6 N) to pH 1 and extracted with EtOAc (20 mL×4). The combined EtOAcextracts were dried over sodium sulfate and concentrated to give 0.51 gof crude S1-2: 1H NMR (400 MHz, CDCl₃) δ 7.06 (dd, J=9.8, 8.5 Hz, 1H),6.75 (dd, J=9.8, 3.7 Hz, 1H), 3.86 (s, 3H), 2.34 (d, J=2.4 Hz, 3H); MS(ESI) m/z 185.12 (M+H).

Oxalyl chloride (0.95 mL, 11.10 mmol, 5.5 equiv) was added to adichloromethane solution (15 mL, anhydrous) of S1-2 (0.51 g, 2.00 mmol,1.0 equiv). DMF (0.1 mL) was added to the resulting mixture. Thereaction was stirred at 25° C. for 1 h and concentrated. The resultingsolid was redissolved in 15 mL of anhydrous dichloromethane Phenol (0.52g, 5.50 mmol, 2.8 equiv), DMAP (0.67 g, 5.60 mmol, 2.8 equiv), andtriethylamine (1.90 mL, 13.90 mmol, 7.0 equiv) were added to thereaction mixture. The reaction was stirred at 25° C. for 12 hrs andconcentrated. EtOAc and H₂O were added to the residue. The organic layerwas washed with aqueous NaOH (1 N), H₂O, and brine, dried over sodiumsulfate, and concentrated. Flash chromatography on silica gel (40:1hexanes/EtOAc) yielded 0.40 g of compound S1-3 (52%, 2 steps): ¹H NMR(400 MHz, CDCl₃) δ 7.47-7.41 (m, 2H), 7.31-7.24 (m, 3H), 7.08 (dd,J=9.2, 9.2 Hz, 1H), 6.77 (dd, J=9.2, 3.7 Hz, 1H), 3.88 (s, 3H), 2.36 (d,J=2.3 Hz, 3H); MS (ESI) m/z 261.12 (M+H).

BBr₃ (1.85 mL, 1 M/dichloromethane, 1.85 mmol, 1.2 equiv) was added to adichloromethane solution (8 mL) of S1-3 (0.40 g, 1.54 mmol, 1.0 equiv)at −78° C. The reaction was stirred from −78° C. to 25° C. for 1.5 hrs,quenched by saturated aqueous NaHCO₃, and concentrated. EtOAc and H₂Owere added to the reaction mixture. The aqueous layer was extracted withEtOAc. The combined Et(O)Ac extracts were dried over sodium sulfate andconcentrated under reduced pressure to yield 0.36 g of crude S1-4: ¹HNMR (400 MHz, CDCl₃) δ 10.66 (s, 1H), 7.50-7.44 (m, 2H), 7.36-7.31 (m,1H), 7.26-7.18 (m, 3H), 6.86 (dd, J=9.3, 4.9 Hz, 1H), 2.60 (d, J=2.4 Hz,3H); MS (ESI) m/z 245.11 (M−H).

Compound S1-4 (4.92 g, 95% purity, 20.00 mmol, 1.0 equiv) was dissolvedin acetic acid (50 mL). Bromine (1.54 mL, 30.00 mmol, 1.5 equiv) wasadded via syringe at rt. After stirring at rt for 2 hrs, LC/MS indicatedthat the starting material was consumed. The reaction mixture wasdiluted with EtOAc, washed with water (3×100 mL) and brine, dried oversodium sulfate, filtered, and concentrated under reduced pressure togive 7.06 g of compound S1-5 as a light yellow solid: ¹H NMR (400 MHz,CDCl₃) δ 11.14 (s, 1H), 7.52 (d, J=9.2 Hz, 1H), 7.49-7.43 (m, 2H),7.36-7.30 (m, 1H), 7.21-7.16 (m, 2H), 2.55 (d, J=2.3 Hz, 3H).

Compound S1-5 (crude, 1.06 g, 2.97 mmol, 1.0 equiv) was dissolve inacetone (20 mL), added with potassium carbonate (0.82 g, 5.94 mmol, 2.0equiv), and cooled to 0° C. in an ice-bath. Benzyl bromide (540 μL, 4.45mmol, 1.5 equiv) was added dropwise. After 2 hrs, LC/MS indicated that40% of the starting material was consumed. The reaction mixture washeated to 50° C. for another hour and the starting material wascompletely consumed. The reaction mixture was diluted with EtOAc (100mL), washed with water and brine, dried over sodium sulfate, filtered,and concentrated under reduced pressure to give 2.2 g of crude S1-6,which was purified by column chromatography (Biotage 10 g column, 2 to5% EtOAc in hexanes gradient), yielding 1.03 g (84%, two steps) of thepure compound S1-6 as an colorless oil: ¹H NMR (400 MHz, CDCl₃) δ7.50-7.47 (m, 2H), 7.40-7.33 (m, 6H), 7.25 (t, J=7.3 Hz, 1H), 7.04 (d,J=8.6 Hz, 2H), 5.09 (s, 2H), 2.32 (d, J=1.8 Hz, 3H).

An LDA/THF solution was prepared by adding n-BuLi (1.6 M/hexanes, 5.10mL, 8.16 mmol, 1.5 equiv) to diisopropylamine (1.15 mL, 8.16 mmol, 1.5equiv) in THF (15 mL) at −78° C. The reaction mixture was warmed to −20°C. and stirred for 15 min. After the LDA solution was cooled to −78° C.,compound S1-6 (2.26 g, 5.44 mmol, 1.0 equiv) in THF (5 mL) was addeddropwise. An orange-red solution was formed. After 10 min, DMF (1.26 mL,16.30 mmol, 3.0 equiv) was added dropwise. The reaction solution wasallowed to warm to −20° C. in 1 h and quenched by saturated aqueousNH₄Cl. LC/MS indicated that the starting material was consumed. Thereaction mixture was diluted with EtOAc (100 mL), washed with water andbrine, dried over sodium sulfate, filtered, and concentrated underreduced pressure. This gave 2.42 g of crude S1-7, which was purified bycolumn chromatography (Biotage 24 g column, 5 to 10% EtOAc in hexanesgradient), yielding 2.23 g (92%) of the pure compound S1-7 as a lightyellow solid: ¹H NMR (400 MHz, CDCl₃) δ 10.37 (s, 1H), 7.51-7.47 (m,2H), 7.40-7.33 (m, 5H), 7.27 (t, J=7.3 Hz, 1H), 7.06-7.02 (m, 22H), 5.12(s, 2H), 2.37 (d, J=2.3 Hz, 3H).

To a solution of compound S1-7 (10 g, 22.60 mmol, 1.0 equiv) in MeOH wasadded trimethylorthoformate (4.8 g, 45.20 mmol, 2.0 equiv) and TsOH.H₂O(0.13 g, 0.68 mmol, 0.03 equiv) at rt. The reaction mixture was heatedto reflux overnight and concentrated under reduced pressure. The residuewas diluted with H₂O and extracted with EtOAc. The organic layer wasdried over sodium sulfate and evaporated to dryness. The crude productwas purified by column chromatography on silica gel (petroleumether:EtOAc from 100:1 to 30:1) to afford compound S1-8 as a lightyellow solid (10 g, 91%): ¹H NMR (400 MHz, CDCl₃) δ 7.41-7.45 (m, 2-1),7.25-7.35 (m, 5H), 7.16-7.21 (m, 1H), 6.98 (d, J=8.0 Hz, 2H), 5.71 (s,1H), 5.04 (s, 2H), 3.46 (s, 6H), 2.29 (d, J=2.4 Hz, 3H).

Compound S1-8 (1.37 g, 2.80 mmol, 3.0 equiv) and enone S1-9 (0.45 g,0.93 mmol, 1.0 equiv) were dissolved in dry THF (5 mL) under N₂. Freshlyprepared LDA/TMEDA/THF (0.71 M/THF, 7.9 mL, 5.60 mmol, 2.0 equiv) wasadded to the solution at −78° C. The solution was stirred at −78° C. forabout 10 min, and then the temperature was slowly increased from −78° C.to −10° C. over 20 min. The reaction mixture was quenched by saturatedaqueous NH₄Cl (50 mL) and extracted with EtOAc (50 ml×3). The organicphase was dried over sodium sulfate and evaporated under reducedpressure to afford the crude product. The crude product was purified bycolumn chromatography on silica gel (petroleum ether:EtOAc: from 50:1 to15:1) to give the desired compound S1-10 (0.60 g, 0.68 mmol, 74%): ¹HNMR (400 MHz, CD₃OD) δ 15.97 (s, 1H), 7.61-7.59 (m, 2H), 7.55-7.53 (m,2H)

(m, 6H), 5.83 (s, 1H), 5.40 (s, 2H), 5.02-4.97 (m, 2H)

Hz, 1H), 3.57 (s, 6H), 3.35-3.26 (m, 1H), 3.09-2.95 (m, 1H), 2.67-2.58(m, 1H), 2.53 (s, 6H), 2.50-2.39 (m, 1H), 2.21-210 (m, 1H), 1.58 (s,9H), 0.31 (s, 3H), 0.16 (s, 3H); MS (ESI) m/z 877.3 (M+H).

Preparation of LDA/TMEDA/THF: To diisopropylamine (1.1 g, 10.90 mmol,1.0 equiv) and TMEDA (5 mL) in dry THF (5 mL) at −78° C. was addedn-BuLi (4.8 mL, 2.5 M/hexanes, 12.00 mmol, 1.1 equiv) dropwise under N₂.The solution was stirred at −78° C. for 1 h. The prepared LDA/TMEDA/THFsolution was about 0.71 M and was used immediately.

Compound S1-10 (50 mg, 0.057 mmol, 1.0 equiv) was dissolved in drydichloromethane (1 mL). TFA (0.5 mL) was added. The solution was stirredat 10° C. for 1 h. LC-MS analysis showed the complete consumption ofstarting material. The reaction mixture was washed with H₂O (10 mL×3)and concentrated under reduced pressure to give crude S1-11, which wasused for the next step without further purification: MS (ESI) m/z 741.1(M+H).

Compound S1-11 (crude, 0.057 mmol, 1.0 equiv) was dissolved in1,2-dichloroethane (2 mL). HOAc (20 μL) and n-propylamine (49 mg, 0.34mmol, 6.0 equiv) were added. The mixture was stirred for 1 h. Na(OAc)₃BH(73 mg, 0.34 mmol, 6.0 equiv) was added and the resulting mixture wasstirred for another hour. The mixture was washed with H₂O (10 mL) andconcentrated to give crude S1-12-1, which was used for the next stepwithout further purification: MS (ESI) m/z 786.2 (M+H).

Compound S1-12-1 (crude, 0.057 mmol, 1.0 equiv) was dissolved in1,2-dichloroethane (2 mL). HOAc (20 μL) and propionaldehyde (49 mg, 0.34mmol, 6.0 equiv) were added. The mixture was stirred for 1 h. Na(OAc)₃BH(73 mg, 0.34 mmol, 6.0 equiv) was added and the resulting mixture wasstirred for another hour. The mixture was washed with H₂O (10 mL) andconcentrated to give crude S1-12-2, which was used for the next stepwithout further purification: MS (ESI) m/z 828.2 (M+H).

Compound S1-12-2 (crude, 0.057 mmol, 1.0 equiv) was dissolved in THF (5mL) in a polypropylene tube at rt. Aqueous HF (2 mL, 48-50%) was added.The reaction mixture was stirred at rt for 1 h. The resulting mixturewas carefully poured into an aqueous solution of K₂HPO₄. The pH of themixture was adjusted to 7-8 by adding more aqueous K₂HPO₄. The mixturewas extracted with EtOAc (20 mL), and the EtOAc extract was concentratedto give crude S1-13-2, which was used for the next step without furtherpurification: MS (ESI) m/z 714.0 (M+H).

Compound S1-13-2 (crude, 0.057 mmol, 1.0 equiv) was dissolved in MeOH (5mL). HCl/MeOH (1 mL, 4 M) and 10% Pd—C (15 mg) was added. The reactionmixture was purged with hydrogen and stirred under H₂ (balloon) at rtfor 1 h. The mixture was filtered and concentrated. The crude compoundwas purified by preparative HPLC using similar conditions for S2-4-1 toafford the desired compound S1-14-2 as a yellow solid (10 mg, 32%, 5steps): ¹H NMR (400 MHz, CD₃OD) δ 7.06 (d, J=6.0 Hz, 1H), 4.41 (s, 2H),4.10 (s, 1H), 3.18-2.91 (m, 13H), 2.37-2.23 (m, 2H), 1.83-1.73 (m, 4H),1.67-1.58 (m, 1H), 0.96 (t, J=7.2 Hz, 3H); MS (ESI) m/z 546.2 (M+H).

Similarly, compound S1-14-1 was prepared directly from S1-12-1 via HFtreatment followed by hydrogenation: ¹H NMR (400 MHz, CD₃OD) δ 7.03 (d,J=6.0 Hz, 1H), 4.27 (s, 2H), 4.12 (s, 1H), 3.21 (dd, J=15.1, 4.6 Hz,1H), 3.05 (s, 3H), 2.97 (s, 3H), 2.94 (d, J=6.9 Hz, 2H), 3.14-2.98 (m,2H), 2.21-2.39 (m, 2H), 1.82-1.71 (m, 2H), 1.70-1.58 (m, 1H), 1.02 (t,J=7.6 Hz, 3H); MS (ESI) m/z 504.44 (M+H).

Compound S1-11 (crude, 0.057 mmol, 1.0 equiv) was dissolved in1,2-dichloroethane (2 mL). HOAc (20 μL) and(S)-(+)-2-(methyoxymethyl)pyrrolidine (49 mg, 0.34 mmol, 6.0 equiv) wereadded. The mixture was stirred at rt for 1 h. Na(OAc)₃BH (73 mg, 0.34mmol, 6.0 equiv) was added and the resulting mixture was stirred foranother hour. The mixture was washed with H₂O (10 mL) and concentratedto give crude S1-12-3, which was used for the next step without furtherpurification: MS (ESI) m/z 842.3 (M+H).

Compound S1-12-3 (crude, 0.057 mmol, 1.0 equiv) was dissolved in THF (5mL) in a polypropylene tube at rt. Aqueous HF (2 mL, 48-50%) was added.The reaction mixture was stirred at rt for 1 h. The resulting mixturewas poured into an aqueous solution of K₂HPO₄. The pH of the mixture wasadjusted to 7-8 with more aqueous K₂HPO₄. The mixture was extracted withEtOAc (20 mL), and the EtOAc extract was concentrated to give crudeS1-13-3, which was used for the next step without further purification:MS (ESI) m/z 728.2 (M+H).

Compound S1-13-3 (crude, 0.057 mmol, 1.0 equiv) was dissolved in MeOH (5mL). HCl/MeOH (1 mL, 4 M) and 100% Pd—C (15 mg) was added. The reactionmixture was purged with hydrogen and stirred under H₂ (balloon) at rtfor 1 h. The mixture was filtered and concentrated. The crude productwas purified by preparative HPLC using similar conditions for S2-4-1 toafford the desired compound S1-14-3 as a yellow solid (10 mg, 31%, 4steps): ¹H NMR (400 MHz, CD₃OD) δ 7.03 (d, J=5.6 Hz, 1H), 4.68 (d,J=13.2 Hz, 1H), 4.29 (d, J=13.2 Hz, 1H), 4.10 (s, 1H), 3.85-3.82 (m,1H), 3.71-3.59 (m, 2H), 3.46-3.41 (m, 1H), 3.39 (s, 3H), 326-2.93 (m,10H), 2.33-2.24 (m, 3H), 2.22-2.09 (m, 1H), 1.95-1.81 (m, 2H), 1.63-1.55(m, 1H); MS (ESI) m/z 560.1 (M+H).

The following compounds were prepared similarly to S1-14-1, S1-14-2, orS1-14-3.

S1-14-4:

¹H NMR (400 MHz, CD₃OD with DCl) δ 7.09 (d, J=5.96 Hz, 1H), 4.23 (s,2H), 4.16 (s, 1H), 3.26-2.94 (m, 9H), 2.38-2.20 (m, 5H), 2.12-2.00 (m,6H), 1.84-1.71 (m, 6H), 1.70-1.56 (m, 1H); MS (ESI) m/z 596.18 (M+H).

S1-14-5:

¹H NMR (400 MHz, CD₃OD with DCl) δ 7.09 (d, J=5.5 Hz, 1H), 4.89-4.79 (m,1H), 4.17 (s, 1H), 3.98-3.89 (m, 1H), 3.26-2.94 (m, 9H), 2.74 (s, 3H),2.38-2.05 (m, 1H), 1.84-1.71 (m, 6H), 1.70-1.56 (m, 1H); MS (ESI) m/Z610.19 (M+H).

S1-14-6:

¹H NMR (400 MHz, CD₃OD) δ 7.08 (d, J=6.0 Hz, 1H), 4.40 (d, J=14.2 Hz,1H), 4.34 (d, J=14.2 Hz, 1H), 4.10 (s, 1H), 3.21 (dd, J=15.5, 4.6 Hz,1H), 3.04 (s, 3H), 2.95 (s, 3H), 3.17-2.97 (m, 2H), 2.34 (t, J=14.7 Hz,1H), 2.28-2.20 (m, 1H), 1.69-1.59 (m, 1H), 1.34 (d, J=6.9 Hz, 3H), 1.00(s, 9H); MS (ESI) m/z 546.30 (M+H).

S1-14-7:

¹H NMR (400 MHz, CD₃OD) δ 7.04 (d, J=6.0 Hz, 1H), 4.40 (d, J=14.2 Hz,1H), 4.29 (d, J=14.2 Hz, 1H), 4.10 (s, 1H), 3.21 (dd, J=15.5, 4.6 Hz,1H), 3.04 (s, 3H), 2.96 (s, 3H), 3.17-2.97 (m, 2H), 2.73 (m, 1H), 2.34(t, J=14.7 Hz, 1H), 2.23 (m, 1H), 1.69-1.59 (m, 1H), 1.46 (d, J=6.9 Hz,3H), 1.00 (s, 9H), 1.07-0.99 (m, 1H), 0.79-0.72 (m, 2H), 0.63-0.55 (m,1H), 0.41-0.32 (m, 1H); MS (ESI) m/z 530.25 (M+H).

S1-14-8:

¹H NMR (400 MHz, CD₃OD) δ 7.09 (d, J=6.0 Hz, 1H), 4.69 (dd, J=30.2, 13.3Hz, 1H), 4.20 (dd, J=30.2, 13.3 Hz, 1H), 4.11 (s, 1H), 3.05 (s, 3H),2.97 (s, 3H), 3.26-2.97 (m, 3H), 2.85 (d, J=21.1 Hz, 3H), 2.36 (t,J=14.6 Hz, 1H), 2.29-2.21 (m, 1H), 1.69-1.60 (m, 1H), 1.52 (t, J=5.0 Hz,3H), 1.30-1.12 (m, 1H), 0.90-0.74 (m, 2H), 0.72-0.64 (m, 1H), 0.59-0.51(m, 1H), 0.49-0.37 (m, 1H); MS (ESI) m/z 544.28 (M+H).

S1-14-9:

¹H NMR (400 MHz, CD₃OD) δ 7.08 (d, J=6.0 Hz, 1H), 4.73 (dd, J=29.8, 13.3Hz, 1H), 4.25 (dd, J=30.2, 13.3 Hz, 1H), 4.10 (s, 1H), 3.05 (s, 3H),2.97 (s, 3H), 3.50-2.97 (m, 5H), 2.36 (t, J=14.6 Hz, 1H), 2.28-2.20 (m,1H), 1.70-1.60 (m, 1H), 1.48 (dd, J=18.3, 6.4 Hz, 3H), 1.29 (dt, J=30.7,6.4 Hz, 1H), 0.90-0.73 (m, 2H), 0.65-0.49 (m, 2H), 0.46-0.37 (m, 1H); MS(ESI) m/z 558.29 (M+H).

S1-14-10:

¹H NMR (400 MHz, CD₃OD) δ 7.06 (d, J=6.0 Hz, 1H), 4.58 (d, J=13.2 Hz,1H), 4.17 (d, J=13.2 Hz, 1H), 4.11 (s, 1H), 3.63-3.55 (m, 1H), 3.05 (s,3H), 2.97 (s, 3H), 3.25-2.97 (m, 5H), 2.36 (t, J=14.7 Hz, 1H), 2.30-2.22(m, 1H), 1.71-1.61 (m, 1H), 1.36 (d, J=6.9 Hz, 3H), 1.21 (s, 9H); MS(ESI) m/z 574.32 (M+H)

S1-14-11:

¹H NMR (400 MHz, CD₃OD) δ 7.08 (d, J=6.0 Hz, 1H), 4.39 (t, J=13.3 Hz,2H), 4.13 (s, 1H), 3.93 (dd, J=12.3, 2.7 Hz, 1H), 3.80 (dd, J=12.4, 6.9Hz, 1H), 3.06 (s, 3H), 2.97 (s, 3H), 3.23-2.97 (m, 4H), 2.37-2.23 (m,2H), 2.22-2.16 (m, 1H), 2.13 (d, J=1.4 Hz, 1H), 1.68-1.58 (m, 1H), 1.06(dd, J=23.4, 6.4 Hz, 6H); MS (ESI) m/z 548.25 (M+H).

S1-14-12:

¹H NMR (400 MHz, CD₃OD) δ 7.10 (d, J=6.0 Hz, 1H), 4.48 (m, 2H), 4.13 (s,1H), 3.98 (dd, J=12.4, 2.7 Hz, 1H), 3.85 (dd, J=11.0, 7.8 Hz, 1H), 3.06(s, 3H), 2.98 (s, 3H), 3.23-2.97 (m, 4H), 2.40-2.23 (m, 2H), 2.10 (d,J=1.4 Hz, 1H), 1.69-1.59 (m, 1H), 1.06 (s, 9H); MS (ESI) m/z 562.26(M+H).

S1-14-13:

¹H NMR (400 MHz, CD₃OD) δ 7.11 (br, s, 1H), 4.71 (d, J=13.3 Hz, 1H),4.39 (d, J=13.3 Hz, 1H), 4.13 (s, 1H), 4.04-3.88 (m, 2H), 3.80 (dd,J=12.4, 6.9 Hz, 1H), 3.06 (s, 3H), 2.97 (s, 3H), 3.23-2.92 (m, 7H),2.47-2.23 (m, 3H), 1.69-1.59 (m, 1H), 118-1.02 (m, 6H); MS (ESI) m/z562.27 (M+H).

S1-14-14:

¹H NMR (400 MHz, CD₃OD) δ 6.98 (d, J=5.5 Hz, 1H), 4.25 (d, J=14.7 Hz,1H), 4.05 (d, J=14.7 Hz, 1H), 4.08 (s, 1H), 3.81-3.73 (m, 1H), 3.04 (s,3H), 2.96 (s, 3H), 3.27-2.97 (m, 4H), 2.76 (m, 1H), 2.35-2.17 (m, 3H),2.09-1.99 (m, 1H), 1.99-1.87 (m, 2H), 1.69-1.59 (m, 1H); MS (ESI) m/z584.26 (M+H).

S1-14-15:

¹H NMR (400 MHz, CD₃OD) δ 7.06 (d, J=5.9 Hz, 1H), 4.27 (s, 2H), 4.12 (s,1H), 3.02 (s, 3H), 3.27-2.96 (m, 8H), 2.40-224 (m, 2H), 1.87-1.58 (m,7H), 1.40-1.19 (m, 3H), 1.11-0.98 (m, 2H); MS (ESI) m/z 558.31 (M+H).

S1-14-16:

¹H NMR (400 MHz, CD₃OD) δ 7.10 (d, J=5.5 Hz, 1H), 4.45 (s, 2H), 4.10 (s,1H), 3.27-2.98 (m, 7H), 3.04 (s, 3H), 2.97 (s, 3H), 2.37 (t, J=15.1 Hz,1H), 2.27-2.17 (m, 1H), 2.14 (s, 3H), 1.70-1.60 (m, 1H); MS (ESI) m/z573.26 (M+H).

S1-14-17:

¹H NMR (400 MHz, CD₃OD) δ 7.11 (d, J=5.5 Hz, 1H), 4.47 (s, 2H), 4.09 (s,1H), 3.27-2.98 (m, 7H), 3.04 (s, 3H), 2.97 (s, 3H), 2.96 (s, 3H), 2.36(t, J=15.1 Hz, 1H), 2.26-2.18 (m, 1H), 1.70-1.60 (m, 1H); MS (ESI) m/z609.20 (M+H).

S1-14-18:

¹H NMR (400 MHz, CD₃OD) δ 7.09 (d, J=6.0 Hz, 1H), 4.77 (d, J=13.3 Hz,1H), 4.55 (d, J=13.3 Hz, 1H), 4.12-4.06 (m, 3H), 3.14 (s, 3H), 3.04 (s,3H), 2.96 (s, 3H), 3.23-2.97 (m, 4H), 2.42-3.34 (m, 1H), 2.23 (m, 1H),1.70-1.60 (m, 1H), 1.02 (s, 9H); MS (ESI) m/z 576.27 (M+H).

S1-14-19:

¹H NMR (400 MHz, CD₃OD) δ 7.09 (d, J=5.5 Hz, 1H), 4.53 (s, 2H), 4.08 (s,1H), 3.90 (s, 2H), 3.67-3.55 (m, 4H), 3.27-2.98 (m, 3H), 3.04 (s, 3H),2.96 (s, 3H), 2.38 (t, J=15.1 Hz, 1H), 2.27-2.19 (m, 1H), 1.70-1.60 (m,1H); MS (ESI) m/z 545.19 (M+H).

S1-14-20:

¹H NMR (400 MHz, CD₃OD) δ 7.03 (d, J=5.9 Hz, 1H), 4.51 (d, J=4.1 Hz,2H), 4.07 (s, 1H), 3.03 (s, 3H), 2.95 (s, 3H), 3.25-2.96 (m, 3H), 2.35(t, J=15.1 Hz, 1H), 2.26-2.18 (m, 1H), 1.70-1.60 (m, 1H), 1.59-1.51 (m,1H), 1.02-0.94 (m, 2H), 0.86-0.78 (m, 2H), 0.76-0.68 (m, 2H), 0.43-0.35(m, 2H); MS (ESI) m/z 542.29 (M+H).

S1-14-21:

¹H NMR (400 MHz, CD₃OD) δ 7.07 (d, J=5.5 Hz, 1H), 4.41 (s, 2H), 4.08 (s,1H), 3.72-3.64 (m, 2H), 3.24-2.98 (m, 5H), 3.04 (s, 3H), 2.96 (s, 3H),2.65-2.55 (m, 1H), 2.37 (t, J=15.1 Hz, 1H), 2.24-2.10 (m, 3H), 1.90-1.77(m, 2H), 1.71-1.61 (m, 1H); MS (ESI) m/z 598.30 (M+H).

S1-14-22:

¹H NMR (400 MHz, CD₃OD) δ 7.01 (d, J=6.0 Hz, 1H), 4.32 (s, 2H), 4.09 (s,1H), 3.87 (s, 2H), 3.24-2.98 (m, 3H), 3.04 (s, 3H), 2.96 (s, 3H), 2.35(t, J=15.1 Hz, 1H), 1.98, (s, 1.5H), 1.70-1.60 (m, 1H); MS (ESI) m/z519.23 (M+H).

S1-14-23:

¹H NMR (400 MHz, CD₃OD) δ 7.06 (d, J=5.5 Hz, 1H), 4.34 (s, 2H), 4.08 (s,1H), 3.58-3.50 (m, 2H), 3.24-2.98 (m, 5H), 3.03 (s, 3H), 2.96 (s, 3H),2.36 (t, J=15.1 Hz, 1H), 2.23 (m, 1H), 2.02-1.92 (m, 2H), 1.69-1.59 (m,1H), 1.54-1.40 (m, 3H), 1.40-1.32 (m, 1H), 0.91 (d, J=6.4 Hz, 6H); MS(ESI) m/z 572.27 (M+H).

S1-14-24:

¹H NMR (400 MHz, CD₃OD) δ 7.07 (d, J=6.0 Hz, 1H), 4.51-2.43 (m, 2H),4.08 (s, 1H), 4.04 (s, 2H), 3.24-2.98 (m, 3H), 3.03 (s, 3H), 2.96 (s,3H), 2.92 (s, 3H), 2.35 (t, J=15.1 Hz, 1H), 2.28-2.18 (m, 1H), 1.69-1.59(m, 1H); MS (ESI) m/z 533.29 (M+H).

S1-14-25:

¹H NMR (400 MHz, CD₃OD) δ 7.07 (d, J=5.5 Hz, 1H), 4.31 (s, 2H), 4.10 (s,1H), 3.05 (s, 3H), 2.97 (s, 3H), 3.27-2.96 (m, 3H), 2.77 (s, 2H), 2.61(s, 1H), 2.36 (t, J=15.1 Hz, 1H), 2.28-2.20 (m, 1H), 1.84-1.76 (m, 4H),1.75-1.66 (m, 5H), 1.63 (br, s, 5H), 1.59 (br, s, 2H); MS (ESI) m/z610.28 (M+H).

S1-14-26:

¹H NMR (400 MHz, CD₃OD) δ 7.07 (br, s, 1H), 4.37 (s, 2H), 4.07 (s, 1H),3.92-2.84 (m, 1H), 3.61-3.54 (m, 2H), 3.24-2.98 (m, 5H), 3.03 (s, 3H),2.96 (s, 3H), 2.36 (t, J=15.1 Hz, 1H), 2.24-2.10 (m, 2H), 2.18-1.96 (m,1H), 1.91 (s, 3H), 1.80-1.59 (m, 3H); MS (ESI) m/z 587.24 (M+H).

S1-14-27:

¹H NMR (400 MHz, CD₃OD) δ 7.03 (d, J=5.5 Hz, 1H), 4.24 (s, 2H), 4.09 (s,1H), 3.04 (s, 3H), 2.96 (s, 3H), 3.27-2.96 (m, 4H), 2.57 (d, J=4.2 Hz,1H), 2.43 (s, 1H), 2.34 (t, J=15.1 Hz, 1H), 2.27-2.19 (m, 1H), 1.87 (dd,J=13.7, 7.8 Hz, 1H), 1.73-1.52 (m, 5H), 1.35 (d, J=11.0 Hz, 1H),1.28-1.20 (m, 2H); MS (ESI) m/z 556.30 (M+H).

S1-14-28:

¹H NMR (400 MHz, CD₃OD) δ 7.07 (d, J=5.9 Hz, 1H), 4.31 (s, 2H), 4.09 (s,1H), 3.47 (s, 1H), 3.04 (s, 3H), 2.96 (s, 3H), 3.27-2.96 (m, 3H), 2.57(d, J=4.2 Hz, 1H), 2.43 (s, 1H), 2.35 (t, J=15.5 Hz, 1H), 2.26 (s, 2H),2.29-2.20 (m, 1H), 2.04-1.89 (m, 6H), 1.87-1.73 (m, 6H), 1.70-1.60 (m,1H); MS (ESI) m/z 596.36 (M+H).

S1-14-29:

¹H NMR (400 MHz, CD₃OD) δ 7.07 (d, J=5.9 Hz, 1H), 4.39 (s, 2H), 4.10 (s,1H), 3.65-3.56 (m, 2H), 3.24-2.98 (m, 5H), 3.04 (s, 3H), 2.97 (s, 3H),2.60-2.52 (m, 1H), 2.37 (t, J=15.1 Hz, 1H), 2.28-2.20 (m, 1H), 2.13-2.02(m, 2H), 1.97-1.88 (m, 2H), 1.70-1.60 (m, 1H); MS (ESI) m/z 573.28(M+H).

S1-14-30:

¹H NMR (400 MHz, CD₃OD) δ 7.25-7.19 (m, 5H), 7.02 (d, J=5.6 Hz, 1H),4.42 (s, 2H), 3.98 (s, 1H), 3.34-3.21 (m, 4H), 3.15-2.85 (m, 11H),2.30-2.18 (m, 2H), 1.62-1.52 (m, 1H), 1.33 (t, J=7.2 Hz, 3H); MS (ESI)m/z 594.1 (M+H).

S1-14-31:

¹H NMR (400 MHz, CD₃OD) δ 7.00 (d, J=5.6 Hz, 1H), 4.88 (t, J=4.4 Hz,1H), 4.55 (t, J=4.4 Hz, 1H), 4.01 (s, 1H), 3.70-3.50 (m, 2H), 3.17 (d,J=7.2 Hz, 2H), 3.10-2.87 (m, 11H), 2.31-2.12 (m, 2H), 1.57-1.54 (m, 1H),1.13-1.08 (m, 1H), 0.74-0.72 (m, 2H), 0.41-0.37 (m, 2H); MS (ESI) m/z562.1 (M+H).

S1-14-32:

¹H NMR (400 MHz, CD₃OD) δ 7.00 (d, J=5.6 Hz, 1H), 4.87 (t, J=4.0 Hz,1H), 4.74 (t, J=4.0 Hz, 1H), 4.43 (s, 2H), 4.02 (s, 1H), 3.60-3.51 (m,2H), 3.20-2.88 (m, 11H), 2.31-2.15 (m, 2H), 1.78-1.7 (m, 2H), 1.58-1.55(m, 1H), 0.93 (m, J=7.2 Hz, 3H); MS (ESI) m/z 550.1 (M+H).

S1-14-33:

¹H NMR (400 MHz, CD₃OD) δ 7.01 (d, J=5.6 Hz, 1H), 4.56 (d, J=13.2 Hz,1H), 4.13 (d, J=13.2 Hz, 1H), 4.01 (s, 1H), 3.56-3.36 (m, 2H), 3.16-2.86(m, 10H), 2.33-2.16 (m, 3H), 2.07-1.91 (m, 2H), 1.73-1.67 (m, L H),1.61-1.52 (m, 1H), 1.42 (d, J=6.4 Hz, 3H); MS (ESI) m/z 575.2 (M+H).

S1-14-34:

¹H NMR (400 MHz, CD₃OD) δ 7.01 (d, J=5.6 Hz, 1H), 4.56 (d, J=13.2 Hz,1H), 4.13 (d, J=13.2 Hz, 1H), 4.01 (s, 1H), 3.56-3.36 (m, 2H), 3.16-2.86(m, 10H), 2.33-2.16 (m, 3H), 2.07-1.91 (m, 2H), 1.73-1.67 (m, 1H),1.61-1.52 (m, 1H), 1.42 (d, J=6.4 Hz, 3H); MS (ESI) m/z 575.2 (M+H).

S1-14-35:

¹H NMR (400 MHz, CD₃OD) δ 7.09 (d, J=6.0 Hz, 1H), 4.96 (t, J=6.0 Hz,1H), 4.78 (t, J=6.0 Hz, 1H), 4.51 (s, 2H), 4.11 (s, 1H), 3.72-3.59 (m,2H), 3.40 (q, J=6.8 Hz, 2H), 3.24-2.97 (m, 9H), 2.39-2.24 (m, 2H),1.69-1.60 (m, 1H), 1.41 (t, J=7.2 Hz, 3H); MS (ESI) m/z 536.1 (M+H).

S1-14-36:

¹H NMR (400 MHz, CD₃OD) δ 7.10 (d, J=6.0 Hz, 1H), 4.62-4.47 (m, 2H),4.12 (s, 1H), 3.50-3.44 (m, 2H), 3.23-2.98 (m, 9H), 2.38-2.25 (m, 2H),1.69-1.66 (m, 1H), 1.55 (s, 3H), 1.42-1.39 (t, J=7.2 Hz, 3H), 1.39-1.35(m, 3H), 094-0.86 (m, 3H); MS (ESI) m/z 544.2 (M+H).

S1-14-37:

¹H NMR (400 MHz, CD₃OD) δ 7.09 (d, J=6.0 Hz, 1H), 4.59 (s, 2H), 4.10 (s,1H), 3.24-2.97 (m, 11H), 2.40-2.24 (m, 2H), 1.70-1.59 (m, 1H), 1.56 (s,3H), 1.21-1.15 (m, 1H), 0.93-0.89 (m, 2H), 0.79-0.77 (m, 2H), 0.69-0.66(m, 1H), 0.59-0.56 (m, 1H), 0.47-0.46 (m, 2H); MS (ESI) m/z 570.1 (M+H).

S1-14-38:

¹H NMR (400 MHz, CD₃OD) δ 7.09 (d, J=6.0 Hz, 1H), 4.63-4.60 (m, 1H),4.50-4.47 (m, 1H), 4.11 (s, 1H), 3.13-2.98 (m, 1H), 2.39-2.24 (m, 2H),1.94-1.92 (m, 1H), 1.75-1.70 (m, 1H); 1.66-1.63 (m, 1H), 1.58 (s, 3H),1.38-1.29 (m, 1H), 1.02 (t, J=7.2 Hz, 3H), 0.92-0.87 (m, 3H); MS (ESI)m/z 558.1 (M+H).

S1-14-39:

¹H NMR (400 MHz, CD₃OD) δ 7.34 (s, 4H), 7.04 (d, J=5.2 Hz, 1H),4.71-4.63 (m, 4H), 4.63 (s, 2H) 3.99 (s, 1H), 3.17-2.87 (m, 9H),2.28-2.15 (m, 2H) 1.61-1.51 (m, 1H); MS (ESI) m/z 564.2 (M+H).

S1-14-40:

¹H NMR (400 MHz, CD₃OD) δ 7.08 (d, J=5.6 Hz, 1H), 4.42 (d, J=4.0 Hz,2H), 4.12 (s, 1H), 3.29-2.90 (m, 13H), 2.41-2.22 (m, 2H), 1.90-1.75 (m,2H), 1.71-1.60 (M, 1H); 1.38 (t, J=7.2 Hz, 3H), 1.05 (t, J=7.2 Hz, 3H);MS (ESI) m/z 530.2 (M+H).

S1-14-41:

¹H NMR (400 MHz, CD₃OD) δ 7.05 (d, J=5.2 Hz, 1H), 4.48 (d, J=13.2 Hz,1H), 4.27 (d, J=13.2 Hz, 1H), 4.09 (d, J=4.4 Hz, 1H), 3.22-2.92 (m,11H), 2.84 (s, 3H), 2.38-2.22 (m, 2H), 1.87-1.70 (m, 2H), 1.68-1.62 (m,1H), 1.03 (t, J=7.2 Hz, 3H); MS (ESI) m/z 518.0 (M+H).

S1-14-42:

¹H NMR (400 MHz, CD₃OD) δ 7.05 (d, J=5.6 Hz, 1H), 4.51 (d, J=13.6 Hz,1H), 4.28 (d, J=13.6 Hz, 1H), 4.09 (s, 1H), 3.20-2.95 (m, 11H), 2.83 (s,3H), 2.40-2.13 (m, 2H), 1.79-1.71 (m, 2H), 1.69-1.57 (m, 1H), 1.46-1.35(m, 2H), 0.98 (t, J=7.2 Hz, 3H); MS (ESI) m/z 532.1 (M+H).

S1-14-43:

¹H NMR (400 MHz, CD₃OD) δ 7.27-7.16 (m, 5H), 7.01 (d, J=5.6 Hz, 1H),4.52-4.48 (m, 1H), 4.29-4.25 (m, 1H), 4.03 (s, 1H), 3.45-3.25 (m, 2H),3.15-2.88 (m, 11H), 2.84 (s, 3H), 2.30-2.16 (m, 2H), 1.60-1.54 (m, 1H);MS (ESI) m/z 580.1 (M+H).

S1-14-44:

¹H NMR (400 MHz, CD₃OD) δ 7.07 (d, J=4.8 Hz, 1H), 4.40 (s, 2H), 4.11 (s,1H), 3.29-2.95 (m, 13H), 2.37-2.23 (m, 2H), 1.79-1.71 (m, 2H), 1.67-1.58(m, 1H), 1.45-1.38 (m, 2H), 1.37 (t, J=7.2 Hz, 3H), 0.95 (t, J=7.2 Hz,3H); MS (ESI) m/z 546.2 (M+H).

S1-14-45:

¹H NMR (400 MHz, CD₃OD) δ 7.03 (d, J=5.6 Hz, 1H), 4.70 (d, J=13.2 Hz,1H), 4.29 (d, J=13.2 Hz, 1H), 4.09 (s, 1H), 3.86-3.83 (m, 1H), 3.73-3.60(m, 2H), 3.49-3.41 (m, 1H), 3.40 (s, 3H), 3.22-2.95 (m, 10H), 2.37-2.26(m, 3H), 2.22-1.84 (m, 3H), 1.68-1.57 (m, 1H); MS (ESI) m/z 560.1 (M+H).

S1-14-46:

¹H NMR (400 MHz, CD₃OD) δ 7.47-7.41 (m, 5H), 6.95 (d, J=6.0 Hz, 1H),4.41-4.36 (m, 2H), 4.34-4.18 (m, 2H), 4.02 (s, 1H), 3.12-2.88 (m, 9H),2.72 (s, 3H), 2.28-2.12 (m, 2H), 1.60-1.50 (m, 1H); MS (ESI) m/z 565.2(M+H).

S1-14-47:

¹H NMR (400 MHz, CD₃OD) δ 7.58-7.49 (m, 5H), 6.99 (d, J=5.6 Hz, 1H),4.49-4.42 (m, 4H), 4.13 (s, 1H), 3.18-2.97 (m, 11H), 2.35-2.23 (m, 2H),1.91-1.88 (m, 2H), 1.68-1.47 (m, 1H), 0.97 (t, J=7.2 Hz, 3H); MS (ESI)m/z 594.2 (M+H).

S1-14-48:

¹H NMR (400 MHz, CD₃OD) δ 7.53-7.49 (m, 5H), 6.96 (d, J=5.2 Hz, 1H),4.62-4.35 (m, 4H), 4.09 (s, 1H), 3.20-2.96 (m, 11H), 2.35-2.21 (m, 2H),1.67-1.48 (m, 1H), 1.26-1.13 (m, 1H), 0.86-0.74 (m, 2H), 0.44-0.33 (m,2H); MS (ESI) m/z 606.1 (M+H).

S1-14-49:

¹H NMR (400 MHz, CD₃OD) δ 7.53-7.48 (m, 5H), 6.96 (d, J=5.6 Hz, 1H),4.48-4.34 (m, 4H), 4.09 (s, 1H), 3.26-2.87 (m, 11H), 2.35-2.20 (m, 2H),1.62-1.56 (m, 1H), 1.44 (t, J=7.2 Hz, 3H); MS (ESI) m/z 580.1 (M+H).

S1-14-50:

¹H NMR (400 MHz, CD₃OD) δ 7.11 (d, J=5.6 Hz, 1H), 5.47 (d, J=52 Hz, 1H),4.55 (s, 2H), 4.12 (s, 1H), 3.95-3.47 (m, 4H), 3.24-2.98 (m, 9H),2.70-2.62 (m, 1H), 2.39-2.25 (m, 3H), 1.69-1.61 (m, 1H); MS (ESI) m/z534.1 (M+H).

S1-14-51:

¹H NMR (400 MHz, CD₃OD) δ 7.10 (d, J=6 Hz, 1H), 5.47 (d, J=52.4 Hz, 1H),4.54 (s, 2H), 4.11 (s, 1H), 3.92-3.39 (m, 4H), 3.26-2.98 (m, 9H),2.70-2.62 (m, 1H), 2.40-2.23 (m, 3H), 1.71-1.62 (m, 1H); MS (ESI) m/z534.1 (M+H).

S1-14-52:

¹H NMR (400 MHz, CD₃OD) δ 6.98 (d, J=5.6 Hz, 1H), 4.07 (s, 1H), 3.93 (s,2H), 3.31 (q, J=9.2 Hz, 2H), 3.19-2.89 (m, 9H), 2.77 (q, J=7.2 Hz, 2H),2.34-2.15 (m, 2H), 1.68-1.57 (m, 1H), 1.11 (t, J=7.2 Hz, 3H); MS (ESI)m/z 572.1 (M+H).

S1-14-53:

¹H NMR (400 MHz, CD₃OD) δ 7.04 (d, J=6.0 Hz, 1H), 4.20 (s, 2H), 4.09 (s,1H), 3.76-3.65 (m, 2H), 3.74 (q, J=7.2 Hz, 2H), 3.20-2.96 (m, 9H), 2.81(d, J=6.8 Hz, 2H), 2.34-2.21 (m, 2H), 1.68-1.56 (m, 1H), 1.07-0.98 (m,1H), 0.65-0.58 (m, 2H), 0.27-0.23 (m, 2H); MS (ESI) m/z 598.1 (M+H).

S1-14-54:

¹H NMR (400 MHz, CD₃OD) δ 6.97 (d, J=6.0 Hz, 1H), 4.45 (s, 2H),4.25-4.17 (m, 4H), 4.09 (s, 1H), 3.21-2.95 (m, 9H), 2.61-2.51 (m, 1H),2.49-2.38 (s, 1H), 2.32-2.18 (m, 2H), 1.65-1.53 (m, 1H); MS (ESI) m/z502.1 (M+H).

S1-14-55:

¹H NMR (400 MHz, CD₃OD) δ 6.98 (d, J. 6.0 Hz, 1H), 4.50-4.42 (m,

), (

H), 4.09 (s, 1H), 3.92-3.85 (m

H), 2.28-2.33 (m, 2H), 1.66 (ddd, J=11.6, 11.2, 11.6 Hz, 1H), 1.33 (d,J=6.8 Hz, 1H), 1.28 (d, J=6.8 Hz 2H); MS (ESI) m/z 516.1 (M+H).

S1-14-56:

¹H NMR (400 MHz, CD₃OD) δ 7.05 (d, J=5.2 Hz, 1H), 4.24 (s, 2H), 4.10 (s,1H), 3.24-2.97 (m, 9H), 2.28-2.23 (m, 2H), 1.98-1.56 (m, 10H), 1.55 (s,3H); MS (ESI) m/z 558.1 (M+H).

S1-14-57:

¹H NMR (400 MHz, CD₃OD) δ 7.36-7.32 (m, 2H), 7.29-7.27 (m, 3H), 7.12 (d,J=5.6 Hz, 1H), 4.53 (s, 2H), 4.11 (s, 1H), 3.40 (t, 2H), 3.28-2.94 (m,13H), 2.43-2.22 (m, 2H), 1.92-1.61 (m, 3H), 1.02 (t, J=7.2 Hz, 3H); MS(ESI) m/z 607.3 (M+H).

S1-14-58:

¹H NMR (400 MHz, CD₃OD) δ 7.26-7.19 (m, 5H), 7.05 (d, J=5.6 Hz, 1H),4.61-4.42 (m, 2H), 4.03 (s, 1H), 3.47-3.33 (rnm, 2H), 3.17 (d, J==7.2Hz, 1H), 3.11-2.88 (m, 11H), 2.32-2.14 (m, 2H), 1.61-1.51 (m, 1H),1.21-1.11 (m, 1H), 0.74-0.72 (m, 2H), 0.41-0.38 (m, 2H); MS (ESI) m/z620.3 (M+H).

S1-14-59:

¹H NMR (400 MHz, CD₃OD) δ 7.00 (d, J=5.6 Hz, 1H), 4.48 (s, 2H), 4.01 (s,1H), 3.87 (t, J=11.6 Hz, 2H), 3.87 (t, J=7.6 Hz, 2H), 3.18-2.88 (m, 9H),2.18-2.07 (m, 2H), 2.33-2.11 (m, 2H), 1.56-1.51 (m, 1H); MS (ESI) m/z552.2 (M+H).

S1-14-60:

¹H NMR (400 MHz, CD₃OD) δ 7.24-7.11 (m, 5H), 7.07 (d, J=4.8 Hz, 1H),4.35 (s, 2H), 4.04 (s, 1H), 3.60-3.57 (m, 3H), 3.16-2.80 (m, 11H),2.31-2.17 (m, 2H), 2.06-1.96 (s, 4H), 1.63-1.52 (m, 1H); MS (ESI) m/z606.2 (M+H).

S1-14-61:

¹H NMR (400 MHz, CD₃OD) δ 7.04 (d, J=5.6 Hz, 1H), 4.35 (s, 2H), 4.03 (s,1H), 3.45-3.40 (m, 2H), 3.23-2.90 (m, 11H), 2.32-2.16 (m, 2H), 2.07-1.81(m, 4H), 1.79-1.65 (m, 4H), 1.63-1.53 (m, 1H); MS (ESI) m/z 544.2 (M+H).

S1-14-62:

¹H NMR (400 MHz, CD₃OD) δ 7.00 (d, J=6.0 Hz, 1H), 4.37 (s, 2H), 4.03 (s,1H), 3.72-3.65 (m, 2H), 3.19-2.84 (m, 11H), 2.82-2.65 (m, 2H), 2.32-2.16(m, 2H), 1.70-1.41 (m, 7H); MS (ESI) m/z 556.2 (M+H).

S1-14-63:

¹H NMR (400 MHz, CD₃OD) δ 7.59-7.34 (m, 5H), 6.94 (d, J=5.6 Hz, 1H),4.63 (s, 2H), 4.10 (s, 1H), 3.19-2.97 (m, 9H), 2.34-2.23 (m, 2H), 1.68(ddd, J=13.2, 13.2, 13.2 Hz 1H) MS (ESI) m/z 538.2 (M+H).

S1-14-64:

¹H NMR (400 MHz, CD₃OD) δ 7.97 (s, 1H), 7.91 (t, J=2.8 Hz, 1H),7.66-7.65 (m, 2H), 6.74 (d, J=5.6 Hz, 1H), 4.46 (s, 2H), 4.00 (s, 1H),3.25-2.88 (m, 9H), 2.27-2.12 (m, 2H), 1.56 (ddd, J=13.6, 13.6, 13.6 Hz,1H); MS (ESI) m/z 539.2 (M+H).

S1-14-65:

¹H NMR (400 MHz, CD₃OD) δ 7.10 (d, J=5.6 Hz, 1H), 4.62 (d, J=13.2 Hz,1H), 4.19 (d, J=13.2 Hz, 1H), 4.17 (s, 1H), 3.41-2.35 (m, 1H), 3.25-2.99(m, 9H), 2.71 (s, 3H), 2.41-2.27 (m, 2H), 2.24-2.17 (m, 2H); 2.05-1.92(m, 2H), 1.78-1.558 (m, 4H), 1.50-1.37 (M, 2H), 1.35-1.20 (m, 1H); MS(ESI) m/z 558.2 (M+H).

S1-14-66:

¹H NMR (400 MHz, CD₃OD) δ 7.07 (d, J=6.0 Hz, 1H), 4.57 (d, J=13.6 Hz,1H), 4.21 (d, J=13.6 Hz, 1H), 4.10 (s, 1H), 3.44-3.35 (m, 1H), 3.30-2.95(m, 11H), 2.38-2.20 (m, 2H), 2.15-2.05 (m, 2H), 2.00-1.90 (m, 2H),1.75-1.55 (m, 4H), 1.50-1.35 (m, 2H), 1.35-1.20 (m, 1H), 1.32 (t, J=7.2Hz, 3H); MS (ESI) m/z 572.2 (M+H).

S1-14-67:

¹H NMR (400 MHz, CD₃OD) δ 7.07 (d, J=5.6 Hz, 1H), 4.56 (d, J=13.6 Hz,1H), 4.25 (d, J=13.6 Hz, 1H), 4.11 (s, 1H), 3.40-3.32 (m, 1H), 3.25-2.95(m, 11H), 2.40-2.21 (m, 2H), 2.17-2.06 (m, 2H), 1.99-1.90 (m, 2H),1.85-1.56 (m, 6H), 1.47-1.20 (m, 3H), 0.96 (t, J=7.2 Hz, 3H); MS (ESI)m/z 586.2 (M+H).

S1-14-68:

¹H NMR (400 MHz, CD₃OD) δ 7.08 (d, J=5.9 Hz, 1H), 4.56 (d, J=12.0 Hz,1H), 4.32 (d, J==12.0 Hz, 1H), 4.11 (s, 1H), 3.56-3.48 (m, 1H),3.21-2.93 (m, 11H), 2.39-2.21 (m, 2H), 2.18-2.04 (m, 2H), 2.0-1.9 (m,2H), 1.81-1.56 (m, 4H), 1.46-1.20 (m, 3H), 1.15-1.03 (s, 1H), 0.78-0.69(m, 2H), 0.45-0.35 (m, 2H); MS (ESI) m/z 598.2 (M+H).

S1-14-69:

¹H NMR (400 MHz, CD₃OD) δ 7.07 (d, J=5.6 Hz, 1H), 4.30 (s, 2H), 4.11 (s,1H), 3.28-2.95 (m, 13H), 2.90-2.79 (m, 1H), 2.40-2.15 (m, 4H), 2.07-1.81(m, 4H), 1.57-1.29 (m, 1H), 1.39-1.33 (t, J=7.2 Hz, 3H); MS (ESI) m/z557.2 (M+H).

S1-14-70:

¹H NMR (400 MHz, CD₃OD) δ 7.05 (d, J=5.6 Hz, 1H), 4.36 (s, 2H), 4.10 (s,1H), 3.28-2.96 (m, 13H), 2.90-2.80 (m, 1H), 2.40-2.14 (m, 4H), 2.06-1.72(m, 6H), 1.67-1.55 (m, 1H), 1.02-0.96 (t, J=7.2 Hz, 3H); MS (ESI) m/z572.2 (M+H).

S1-14-71:

¹H NMR (400 MHz, CD₃OD) δ 7.08 (d, J=5.6 Hz, 1H), 4.55-4.36 (m, 2H),4.12 (s, 1H), 3.43-2.80 (m, 13H), 2.39-2.12 (m, 4H), 2.08-1.80 (m, 5H),1.70-1.56 (m, 1H), 1.21-1.12 (m, 1H), 0.82-0.72 (m, 2H), 0.49-0.39 (m,2H); MS (ESI) m/z 584.2 (M+H).

S1-14-72:

¹H NMR (400 MHz, CD₃OD) δ 6.98 (dd, J=2.0, 6.0 Hz, 1H), 4.55-4.45 (m,3H), 4.45-3.38 (m, 2H), 4.18-4.02 (m, 3H), 3.33 (s, 3H), 3.22-2.95 (m,9H), 2.37-2.22 (m, 2H), 168-158 (m, 1H); MS (ESI) m/z 532.1 (M+H).

S1-14-73:

¹H NMR (400 MHz, CD₃OD) δ 7.14 (d, J=5.6 Hz, 1H), 4.60-4.51 (m, 1H),4.52-4.45 (m, 1H), 4.11 (s, 1H), 3.25-2.92 (m, 11H), 2.41-2.20 (m, 2H),2.08-1.75 (m, 8H), 1.68-1.59 (m, 1H), 1.50 (s, 3H), 1.14 (t, J=7.2 Hz,3H); MS (ESI) m/z 572.2 (M+H).

S1-14-74:

¹H NMR (400 MHz, CD₃OD) δ 7.02 (d, J=5.6 Hz, 1H), 4.25 (s, 2H), 4.11 (s,1H), 3.22-2.98 (m, 11H), 2.36-2.23 (m, 2H), 1.68-1.58 (m, 1H), 1.33 (t,J=7.2 Hz, 3H); MS (ESI) m/z 490.4 (M+H).

S1-14-75:

¹H NMR (400 MHz, CD₃OD) δ 7.08 (d, J=5.6 Hz, 1H), 4.23 (s, 2H), 4.11 (s,1H), 3.25-2.91 (m, 9H), 2.39-2.20 (m, 2H), 2.00-1.75 (m, 8H), 1.68-1.59(m, 1H), 1.49 (s, 3H); MS (ESI) m/z 544.3 (M+H).

S1-14-76:

¹H NMR (400 MHz, CD₃OD) δ 7.10 (d, J=6.0 Hz, 1H), 4.64-4.47 (m, 2H),4.11 (s, 1H), 3.25-2.98 (m, 11H), 2.39-2.24 (m, 2H), 1.98-1.90 (m, 1H),1.80-1.70 (m, 1H), 1.68-1.60 (m, 1H), 1.55 (s, 3H), 1.38-1.29 (m, 1H),1.02 (t, J=7.2 Hz, 3H), 0.98-0.82 (m, 3H); MS (ESI) m/z 558.1 (M+H).

S1-14-77:

¹H NMR (400 MHz, CD₃OD) δ 7.06 (d, J=5.6 Hz, 1H), 4.30 (s, 2H), 4.12 (s,1H), 3.24-2.98 (m, 11H), 2.37-2.25 (m, 2H), 1.69-1.60 (m, 1H), 1.19-1.14(m, 1H), 0.79-0.73 (m, 2H), 0.48-0.42 (m, 2H); MS (ESI) m/z 516.0 (M+H).

S1-14-78:

¹H NMR (400 MHz, CD₃OD) δ 6.97 (d, J=5.6 Hz, 1H), 4.07 (s, 1H), 3.96 (s,2H), 3.38 (t, J=9.6 Hz, 2), 3.20-2.94 (m, 9H), 2.68 (t, J=7.6 Hz, 2H)2.35-2.25 (m, 2H), 1.58-1.50 (m, 3H), 0.88 (t, J=7.2 MHz, 3H); MS (ESI)m/z 586.1 (M+H).

S1-14-79:

¹H NMR (400 MHz, CD₃OD) δ 6.94 (d, J=6.0 Hz, 1H), 4.18 (s, 2H), 4.02 (s,1H), 3.15-2.82 (m, 11H), 2.28-2.15 (m, 2H), 1.66-1.51 (m, 3H), 1.40-1.30(m, 2H), 0.90 (t, J=7.2 Hz, 3H); MS (ESI) m/z 518.1 (M+H).

S1-14-80:

¹H NMR (400 MHz, CD₃OD) δ 6.91 (d, J=5.6 Hz, 1H), 4.12 (s, 2H), 4.00 (s,1H), 3.10-2.84 (m, 11H), 2.62-2.54 (m, 1H), 2.24-2.05 (m, 4H), 1.89-1.71(m, 4H), 1.56-1.47 (m, 1H); MS (ESI) m/z 530.1 (M+H).

S1-14-81:

¹H NMR (400 MHz, CD₃OD) δ 6.92 (d, J=5.2 Hz, 1H), 4.16 (s, 2H), 4.00 (s,1H), 3.10-2.84 (m, 10H), 2.23-2.06 (m, 4H), 1.79-1.76 (m, 2H), 1.61-1.50(m, 2H), 1.32-1.10 (m, 5H); MS (ESI) m/z 530.1 (M+H).

S1-14-82:

¹H NMR (400 MHz, CD₃OD) δ 7.01 (d, J=6.0 Hz, 1H), 4.36 (s, 2H), 4.10 (s,1H), 3.22-2.95 (m, 9H), 2.32-2.23 (m, 2H), 1.67-1.59 (m, 1H), 1.56 (s,3H), 1.12-1.09 (m, 2H), 0.86-0.83 (m, 2H); MS (ESI) m/z 516.0 (M+H).

S1-14-83:

¹H NMR (400 MHz, CD₃OD) δ 7.04 (d, J=5.2 Hz, 1H), 4.86 (d, J=4.4 Hz,1H), 4.72 (d, J=4.4 Hz, 1H), 4.35 (s, 2H), 4.11 (s, 1H), 3.52 (d, J=4.0Hz, 1H), 3.45 (d, J=40 Hz, 1H), 3.23-2.95 (m, 9H), 2.36-2.24 (m, 2H),1.68-1.58 (m, 1H); MS (ESI) m/z 508.0 (M+H).

S1-14-84:

¹H NMR (400 MHz, CD₃OD) δ 7.15 (d, J=5.6 Hz, 1H), 4.61-4.55 (m, 2H),4.30-4.19 (m, 1H), 4.11 (s, 1H), 4.05-3.50 (m, 4H), 3.23-2.90 (m, 15H),2.70-2.60 (m, 1H), 2.55-2.45 (m, 1H), 2.35-2.20 (m, 2H), 1.68-1.57 (m,1H); MS (ESI) m/z 559.1 (M+H).

S1-14-85:

¹H NMR (400 MHz, CD₃OD) δ 7.13 (d, J=6.06 Hz, 1H), 4.55 (s, 2H),4.25-4.18 (m, 1H), 4.09 (s, 1H), 3.95-3.48 (m, 4H), 3.23-2.95 (m, 15H),2.65-2.58 (m, 1H), 2.45-2.39 (m, 1H), 2.38-2.19 (m, 2H), 1.70-1.58 (m,1H); MS (ESI) m/z 559.1 (M+H).

S1-14-86:

¹H NMR (400 MHz, CD₃OD) δ 7.28-7.16 (m, 5H), 6.93 (d, J=6.0 Hz, 1H),4.23 (s, 2H), 4.00 (s, 1H), 3.25 (t, J=7.6 Hz, 2H), 3.21-2.88 (m, 11H),2.28-2.14 (m, 2H), 1.61-1.50 (m, 1H); MS (ESI) m/z 566.1 (M+H).

S1-14-87:

¹H NMR (400 MHz, CD₃OD) δ 7.38-7.27 (m, 5H), 6.90 (d, J=6.0 Hz, 1H),4.20 (s, 2H), 4.10 (s, 1H), 3.20-2.98 (m, 11H), 2.29-2.20 (m, 2H),1.69-1.60 (m, 1H), 1.44 (s, 6H); MS (ESI) m/z 594.0 (M+H).

S1-14-88:

¹H NMR (4.00 MHz, CD₃ D) δ 7.29-7.23 (m, 4H), 7.11 (d, J=6.0 Hz, 1H),4.49-4.43 (m, 3H), 4.10 (s, 1H), 3.57-3.48 (m, 4H), 3.24-2.98 (m, 11H),2.40-2.25 (m, 2H), 1.66-158 (m, 1H), 1.41 (t, J=7.2 Hz, 3H); MS (ESI)m/z 605.9 (M+H).

S1-14-89:

¹H NMR (400 MHz, CD₃OD) δ 7.22-7.16 (m, 4H), 7.05 (d, J=6.0 Hz, 1H),4.48-4.41 (m, 3H), 4.05 (s, 1H), 3.60-3.46 (m, 4H), 3.18-2.95 (m, 11H),2.35-2.17 (m, 2H), 1.82-1.68 (m, 2H), 1.62-1.52 (m, 1H), 0.90 (t, J=7.2Hz, 3H); MS (ESI) m/z 620.3 (M+H).

S1-14-90:

¹H NMR (400 MHz, CD₃OD) δ 7.18-7.10 (m, 4H), 6.95 (d, J=6.0 Hz, 1H),4.25 (s, 2H), 4.11-4.04 (m, 1H), 4.00 (s, 1H), 3.40-3.34 (m, 2H),3.19-2.85 (m, 11H), 2.26-2.12 (m, 2H), 1.57-1.51 (m, 1H); MS (ESI) m/z578.4 (M+H).

S1-14-91:

¹H NMR (400 MHz, CD₃OD) δ 7.10 (d, J=5.6 Hz, 1H), 4.34 (s, 2H), 4.13 (s,1H), 3.20-2.89 (m, 11H), 231-225 (m, 2H), 190-1.73 (m, 6H), 1.60-1.48(m, 3H), 0.86 (t, J=7.2 Hz, 3H); MS (ESI) m/z 558.1 (M+H).

S1-14-92:

¹H NMR (400 MHz, CD₃OD) δ 7.04 (d, J=5.6 Hz, 1H), 4.38 (s, 2H), 4.03 (s,1H), 3.18-2.85 (m, 13H), 2.30-2.15 (m, 2H), 1.90-1.75 (m, 6H),1.70-1.518 (m, 3H), 1.20-1.11 (m, 1H), 0.81 (t, J=7.2 Hz, 3H), 0.78-0.69(m, 2H), 0.45-0.36 (m, 2H); MS (ESI) m/z 612.1 (M+H).

S1-14-93:

¹H NMR (400 MHz, CD₃OD) δ 7.10 (d, J=5.6 Hz, 1H), 4.38-4.34 (m, 2H),4.03 (s, 1H), 3.36-3.29 (m, 1H), 3.19-2.88 (m, 12H), 2.36-2.25 (m, 2H),2.00-1.81 (m, 8H), 1.72-1.50 (m, 3H), 0.91 (t, J=7.2 Hz, 3H), 0.82 (t,J=7.2 Hz, 3H); MS (ESI) m/z 600.2 (M+H).

S1-14-94:

¹H NMR (400 MHz, CD₃OD) δ 7.08 (d, J=5.6 Hz, 1H), 4.38-4.34 (m, 2H),4.11 (s, 1H), 3.38-3.30 (m, 1H), 3.25-2.95 (m, 12H), 2.36-2.25 (m, 2H),2.05-1.85 (m, 6H), 1.78-1.61 (m, 3H), 1.45 (t, J=7.2 Hz, 3H), 0.90 (t,J=7.2 Hz, 3H); MS (ESI) m/z 586.0 (M+H).

S1-14-95:

¹H NMR (400 MHz, CD₃OD) δ 7.01 (d, J=5.2 Hz, 1H), 4.40 (d, J=13.2 Hz,1H), 4.28 (d, J=13.6 Hz, 1H), 4.04 (s, 1H), 3.22-2.81 (m, 13H),2.31-2.17 (m, 2H), 2.06-1.93 (m, 2H), 1.82-1.43 (m, 9H), 1.31 (t, J=7.2Hz, 3H), 1.25-1.14 (m, 3H); MS (ESI) m/z 600.3 (M+H).

S1-14-96:

¹H NMR (400 MHz, CD₃OD) δ 7.02 (d, J=6 Hz, 1H), 4.42-4.29 (m, 2H), 4.05(s, 1H), 3.22-2.81 (m, 13H), 2.31-2.17 (m, 2H), 2.06-1.93 (m, 2H),1.82-1.43 (m, 11H), 1.31 (t, J=7.2 Hz, 3H), 1.25-1.14 (m, 3H); MS (ESI)m/z 600.3 (M+H).

S1-14-97:

¹H NMR (400 MHz, CD₃OD) δ 7.15 (d, J=5.2 Hz, 1H), 4.54 (s, 2H), 4.16 (s,1H), 3.23-3.01 (m, 13H), 2.42-2.29 (m, 2H), 2.14-2.05 (m, 1H), 1.92-1.83(m, 1H), 1.79-1.45 (m, 9H), 1.48-1.21 (m, 4H), 0.86-0.75 (m, 2H),0.55-0.47 (m, 2H); MS (ESI) m/z 626.2 (M+H).

S1-14-98:

¹H NMR (400 MHz, CD₃OD) δ 7.07 (d, J=5.6 Hz, 1H), 4.29 (s, 2H), 4.13 (s,1H), 3.21-2.96 (m, 11H), 2.38-2.25 (m, 2H), 2.02-1.91 (m, 1H), 1.85-1.47(m, 11H), 1.37-1.26 (m, 2H); MS (ESI) m/z 572.2 (M+H).

S1-14-99:

¹H NMR (400 MHz, CD₃OD) δ 6.97 (d, J=5.6 Hz, 1H), 4.31 (s, 2H), 4.00 (s,1H), 3.57-3.44 (m, 3H), 3.27-3.22 (m, 2H), 3.13-2.85 (m, 10H), 2.28-2.21(m, 1H), 2.15-2.08 (m, 2H), 2.04-1.89 (m, 3H), 1.85-1.77 (m, 1H),1.70-1.66 (m, 1H), 1.60-1.48 (m, 1H); MS (ESI) m/z 599.2 (M+H).

S1-14-100:

¹H NMR (400 MHz, CD₃OD) δ 7.03 (d, J=6.0 Hz, 1H), 4.29 (s, 2H), 4.03 (s,1H), 3.40-3.29 (m, 1H), 3.23-2.81 (m, 10H), 2.63-2.56 (m, 1H), 2.32-2.07(m, 4H), 1.62-1.49 (m, 2H), 1.35-1.25 (m, 1H), 1.10 (d, J=7.6 Hz, 3H),0.90 (d, J=7.6 Hz, 3H), 0.89-0.78 (m, 1H); MS (ESI) m/z 558.3 (M+H).

S1-14-101:

¹H NMR (400 MHz, CD₃OD) δ 7.10 (d, J=5.6 Hz, 1H), 4.37 (s, 2H), 4.11 (s,1H), 3.43-3.37 (m, 2H), 3.23-2.97 (m, 9H), 2.68-2.60 (m, 2H), 2.42-2.24(m, 2H), 1.98-1.81 (m, 3H), 1.71-1.58 (m, 1H), 0.99 (d, J=7.6 Hz, 6H),0.95-0.85 (m, 1H); MS (ESI) m/z 558.6 (M+H).

S1-14-102:

¹H NMR (400 MHz, CD₃OD) δ 7.10 (d, J=6.0 Hz, 1H), 4.53-4.48 (m, 2H),4.42-4.38 (m, 1H), 4.10 (s, 1H), 3.92-3.62 (m, 2H), 3.55-3.50 (m, 2H),3.25-2.96 (m, 9H), 2.62-2.51 (m, 1H), 2.40-2.21 (m, 2H), 2.19-2.02 (m,2H), 1.96 (d, J=7.2 Hz, 3H), 1.71-1.60 (m, 1H); MS (ESI) m/z 573.3(M+H).

S1-14-103:

¹H NMR (400 MHz, CD₃OD) δ 7.12 (d, J=60 Hz, 1H), 4.57-4.46 (m, 3H), 4.15(s, 1H), 3.90-3.83 (m, 1H), 3.68-3.51 (m, 3H), 3.24-2.98 (m, 9H),2.62-2.55 (m, 1H), 2.39-2.25 (m, 2H), 2.21-2.05 (m, 2H), 1.98 (d, J=10Hz, 3H), 1.67-1.60 (m, 1H); MS (ESI) m/z 572.9 (M+H).

S1-14-104:

¹H NMR (400 MHz, CD₃OD) δ 7.22-7.16 (m, 4H), 7.02 (d, J=6.0 Hz, 1H),4.52-4.38 (m, 3H), 4.05 (s, 1H), 3.45-3.32 (m, 4H), 3.18-2.95 (m, 11H),2.32-2.15 (m, 2H), 1.61-1.52 (m, 1H), 1.15-1.08 (m, 1H), 0.73-0.67 (m,2H), 0.39-0.33 (m, 2H); MS (ESI) m/z 632.0 (M+H).

S1-14-105:

¹H NMR (400 MHz, CD₃OD) δ 7.44-7.37 (m, 5H), 6.93 (d, J=5.6 Hz, 1H),4.23 (s, 2H), 4.21 (s, 2H), 4.03 (s, 1H), 3.25-2.88 (m, 9H), 2.27-2.15(m, 2H), 1.59-1.50 (m, 1H); MS (ESI) m/z 552.0 (M+H).

S1-14-106:

¹H NMR (400 MHz, CD₃OD) δ 6.97 (d, J=5.6 Hz, 1H), 4.34 (s, 2H), 4.05 (d,J=8.8 Hz, 2H), 4.02 (s, 1H), 3.25-2.88 (m, 9H), 2.30-2.15 (m, 2H),1.61-1.51 (m, 1H); MS (ESI) m/z 544.1 (M+H).

S1-14-107:

¹H NMR (400 MHz, CD₃OD) δ 7.03 (d, J=5.2 Hz, 1H), 4.39 (s, 2H), 4.04 (s,1H), 3.58-3.49 (m, 1H), 3.48-3.44 (m, 1H), 3.18-2.88 (m, 11H), 2.32-2.15(m, 2H), 1.98-1.88 (m, 1H), 1.82-1.73 (m, 1H), 1.62-1.41 (m, 5H), 0.82(m, J=7.2 Hz, 3H), 0.78 (m, J=7.2 Hz 3H); MS (ESI) m/z 572.1 (M+H).

S1-14-108:

¹H NMR (400 MHz, CD₃OD) δ 6.99 (t, J=6.0 Hz, 1H), 4.29-4.28 (m, 2H),4.01 (s, 1H), 4.00-398 (m, 1H), 3.33-3.29 (m, 2H), 3.18-2.95 (m, 11H),2.31-2.27 (m, 2H), 2.17-2.04 (m, 2H), 1.95-1.84 (m, 2H), 1.57-1.49 (m,1H); MS (ESI) m/z 546.9 (M+H).

S1-14-109:

¹H NMR (400 MHz, CD₃OD) δ 6.98 (t, J=5.6 Hz, 1H), 4.30-4.28 (m, 2H),4.01 (s, 1H), 4.00-3.98 (m, 1H), 3.55-3.48 (m, 2H), 3.39-3.37 (m, 1H),3.26 (s, 3H), 3.18-2.95 (m, 11H), 2.32-2.16 (m, 3H), 2.06-2.02 (m, 1H),1.85-1.78 (m, 2H), 1.62-1.50 (m, 1H); MS (ESI) m/z 560.0 (M+H)

S1-14-110:

¹H NMR (400 MHz, CD₃OD) δ 7.16 (d, J=6.0 Hz, 1H), 4.55 (d, J=13.2 Hz,1H), 4.39 (d, J=13.2 Hz, 1H), 4.10 (s, 1H), 3.51-3.43 (m, 1H), 3.04 (s,3H), 2.96 (s, 3H), 2.89 (s, 3H), 3.25-2.97 (m, 3H), 2.35 (t, J=14.7 Hz,1H), 2.29-2.21 (m, 1H), 1.69-1.59 (m, 1H), 1.38 (d, J=6.9 Hz, 3H), 1.00(s, 9H); MS (ESI) in m/z 560.25 (M+H).

S1-14-111:

¹H NMR (400 MHz, CD₃OD) δ 7.10 (d, J=6.5 Hz, 1H), 4.55 (d, J=12.2 Hz,1H), 4.44 (d, J=12.2 Hz, 1H), 4.12 (s, 1H), 2.95-3.05 (m, 13H),2.22-2.40 (m, 2H), 1.59-1.75 (m, 3H), 1.35-1.45 (m, 2H), 1.12-1.25 (m,1H), 0.95 (t, J=7.7 Hz, 3H), 0.75-0.85 (m, 2H), 0.40-0.50 (m, 2H); MS(ESI) m/z 572.2 (M+H).

S1-14-112:

¹H NMR (400 MHz, CD₃OD) δ 7.00 (d, J=5.6 Hz, 1H), 4.35 (s, 2H), 4.00 (s,1H), 2.70-3.20 (m, 12H), 2.12-2.31 (m, 2H), 1.50-1.80 (m, 6H), 1.15-1.40(m, 2H), 0.85-0.95 (m, 6H); MS (ESI) m/z 560.1.

S1-14-113:

¹H NMR (400 MHz, CD₃OD) δ 7.07 (d, J=6.0 Hz, 1H), 4.30 (s, 2H), 4.06 (s,1H), 3.23-3.16 (m, 1H), 3.17-2.95 (m, 9H), 2.39-2.30 (m, 2H), 2.26-2.19(m, 1H), 1.90-1.81 (m, 1H), 1.78 (t, J=4.6, 1H), 1.67-1.54 (m, 4H),1.42-1.33 (m, 1H), 1.21 (dd, J=13.7, 4.1 Hz, 1H), 1.01 (s, 3H), 0.93 (s,3H), 0.89 (s, 3H); MS (ESI) m/z 598.33 (M+H)

S1-14-114:

¹H NMR (400 MHz, CD₃OD) δ 7.07 (d, J=6.0 Hz, 1H), 4.37 (d, J=13.3 Hz,1H), 4.20 (d, J=13.3 Hz, 1H), 4.09 (s, 1H), 3.23-3.16 (m, 1H), 3.17-2.96(m, 9H), 2.35 (t, J=14.7 Hz, 1H), 2.28-2.21 (m, 1H), 2.13-2.06 (m, 1H),1.92-1.77 (m, 4H), 1.74-1.60 (m, 2H), 1.24-1.17 (m, 1H), 1.08 (s, 3H),0.98 (s, 3H), 0.92 (s, 3H); MS (ESI) m/z 598.28 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.11 (d, J=5.2 Hz, 1H) 4.37 (s, 2H), 4.07 (s,1H)

(m, 3H), 3.19-2.92 (m, 11H), 2.84 (s, 6H), 2.40-1.98 (m, 6H), 1.63-1.53(m, 1H) MS (ESI) m/z 573.1 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 6.96 (d, J=5.6 Hz, 1H), 4.44-4.33 (m, 2H),4.19 (t, J=8.4 Hz, 1H), 4.02 (s, 1H), 3.59-3.57 (m, 1H), 3.40-3.30 (m,1H), 3.14-3.11 (m, 2H), 3.03-2.88 (m, 7H), 2.56-2.50 (m, 1H), 2.28-2.20(m, 1H), 2.17-2.13 (m, 2H), 1.97-1.90 (m, 2H), 1.60-1.51 (m, 1H); MS(ESI) m/z 559.2 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.11 (d, J=5.2 Hz, 1H), 4.36 (s, 2H), 4.13 (s,1H), 3.56 (d, J=11.6 Hz, 2H), 3.28 (s, 3H), 3.26 (d, J=5.6 Hz, 2H),3.22-2.97 (m, 11H), 2.35-2.25 (m, 2H), 1.98-1.90 (m, 3H), 1.67-1.56 (m,3H); MS (ESI) m/z 574.2 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.30-7.23 (m, 2H), 7.14 (d, J=4.4 Hz, 1H),7.01-6.91 (m, 3H), 4.44 (s, 2H), 4.11 (s, 1H), 3.64 (d, J=12 Hz, 1H),3.45 (s, 3H), 3.23-3.18 (m, 1H), 3.11-2.96 (m, 9H), 2.36-2.16 (m, 6H),1.68-1.61 (m, 1H); MS (ESI) m/z 622.2 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.49 (s, 2H), 7.19 (d, J=5.6 Hz, 1H), 4.46 (s,2H), 4.13 (s, 1H), 3.72 (d, J=12 Hz, 2H), 3.53-3.49 (m, 1H), 3.41-3.35(m, 2H), 3.23-2.98 (m, 9H), 2.39-2.24 (m, 6H), 1.68-1.58 (m, 1H); MS(ESI) m/z 596.2 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.15-7.11 (m, 1H), 4.49 (d, J=9.2 Hz, 2H),4.11 (s, 1H), 3.64-3.60 (m, 1H), 3.49-3.34 (m, 1H), 3.34-3.33 (m, 1H),3.22-2.96 (m, 10H), 2.60-2.51 (m, 1H), 2.43-2.20 (m, 3H), 1.78-1.50 (m,7H), 1.42-1.40 (m, 2H); MS (ESI) m/z 570.2 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.13-7.12 (m, 1H), 4.48 (s, 2H), 4.15 (s, 1H),3.74-3.56 (m, 2H), 3.46-3.37 (m, 3H), 3.28-3.17 (m, 2H), 3.11-2.97 (m,8H), 2.82 (d, J=12.8 Hz, 3H), 2.33-2.26 (m, 2H), 2.17-1.92 (m, 5H), 1.75(d, J=14.4 Hz, 1H), 1.67-1.68 (m, 1H); MS (ESI) m/z 613.3 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.13 (s, 1H), 4.36 (s, 2H), 4.15 (s, 1H), 3.53(d, J=11.2 Hz, 2H), 3.25-2.98 (m, 11H), 2.29 (d, J=13.2 Hz, 2H), 1.94(d, J=14 Hz, 2H), 1.75-1.51 (m, 4H), 1.37-1.23 (m, 4H), 091-0.88 (t,J=6.8 Hz, 3H); MS (ESI) m/z 572.3 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.16 (d, =5.6 Hz, 1H), 4.42 (s, 1H), 4.42 (s,2H), 4.14 (s, 1H), 3.63 (d, J=11.2 Hz, 2H), 3.25-3.12 (m, 6H), 3.07-2.93(m, 13H), 2.40-2.30 (m, 3H), 2.11 (d, J=14 Hz, 2H), 1.74-1.65 (m, 3H),MS (ESI) m/z 587.3 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 6.96 (d, J=4.8 Hz, 1H), 4.59-4.57 (m, 1H),4.41-4.31 (m, 2H), 4.04-3.93 (m, 3H), 3.13-2.88 (m, 9H), 2.50-2.46 (m,1H), 2.28-2.16 (m, 3H), 1.61-1.50 (m, 1H), 1.34 (d, J=4.8 Hz, 3H); MS(ESI) m/z 516.2 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.14 (d, J=5.6 Hz, 1H), 5.04-5.02 (m, 0.5H),4.90-4.88 (m, 0.5H), 4.41 (s, 2H), 4.12 (s, 1H), 3.65-3.33 (m, 4H),3.25-2.97 (m, 9H), 2.37-2.03 (m, 6H), 1.67-1.58 (m, 1H); MS (ESI) m/z548.2 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.11 (d, J=5.6 Hz, 1H), 4.38 (s, 2H), 4.11 (s,1H)

(m, 2H), 3.22-2.97 (m, 11H), 2.36-2.24 (m, 2H), 1.85-1.54 (m, 11H),1.50-1.45 (m, 2H); MS (ESI) m/s 584.3 (M+H)

¹H NMR (400 MHz, CD₃OD) δ 7.10 (d, J=5.6 Hz, 1H), 4.38 (s, 2H), 4.11 (s,1H), 3.40-3.30 (m, 2H), 3.23-2.97 (m, 11H), 2.36-2.24 (m, 2H), 1.90-1.87(m, 2H), 1.64-1.32 (m, 13H); MS (ESI) m/z 597.9 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.11 (d, J=5.6 Hz, 1H), 4.41 (s, 2H), 4.11 (s,1H), 3.54-3.51 (m, 2H), 3.22-2.97 (m, 11H), 2.37-2.18 (m, 4H), 1.68-1.62(m, 1H), 1.22-1.19 (m, 2H), 0.53-0.50 (m, 4H); MS (ESI) m/z 556.2 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.15 (d, J=5.6 Hz, 1H), 4.47 (s, 2H), 4.11 (s,1H), 3.66-3.50 (m, 2H), 3.46-3.32 (m, 2H), 3.22-2.97 (m, 9H), 2.38-2.24(m, 6H), 1.68-1.58 (m, 1H); MS (ESI) m/z 566.2 (M+H).

¹H NMR (400 MHz, MeOD) δ 7.11 and 7.10 (each s, total 1H), 4.50 (s, 2H),4.13 (s, 1H), 3.73-3.64 (m, 2H), 3.27-2.95 (m, 9H), 2.40-2.25 (m, 4H),1.79-1.75 (m, 2H), 1.70-1.60 (m, 1H), 1.42 (d, J=7.2 Hz, 6H); MS (ESI)m/z 544.1 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.04 (d, J=5.6 Hz, 1H), 4.30 (s, 2H), 4.05 (s,1H), 3.29-3.22 (m, 4H), 3.13-2.89 (m, 9H), 2.27-2.17 (m, 2H), 1.85-1.80(m, 2H), 1.72-1.68 (m, 2H), 1.60-1.51 (m, 1H), 1.19 (s, 3H); MS (ESI)m/z 560.0 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.08 (dd, J=11.0, 5.5 Hz, 1H), 4.61 (dd,J=26.7, 14.2 Hz, 1H), 4.47-4.27 (m, 2H), 4.10 (s, 1H), 4.00-3.82 (m,2H), 3.43-3.30 (m, 2H), 3.25-2.94 (m, 11H), 2.42-2.32 (m, 1H), 2.29-2.11(m, 2H), 2.03-1.90 (m, 2H), 1.71-1.56 (m, 2H), 1.38 (t, J=7.3 Hz, 3H);MS (ESI) m/z 574.20 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.53 (d, J=7.6 Hz, 1H), 7.36 (d, J=8.0 Hz,1H), 7.19 (s, 1H), 7.11 (t, J=7.6 Hz, 1H), 7.04-7.00 (m, 2H), 4.33-4.26(m, 2H), 4.11 (s, 1H), 3.42-3.37 (m, 2H), 3.26-2.95 (m, 11H), 2.33-2.23(m, 2H), 1.68-1.59 (m, 1H); MS (ESI) m/z 605.0 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.00 (d, J=5.6 Hz, 1H), 4.24 (s, 2H), 4.02 (s,1H), 3.45-3.42 (m, 2H), 3.11-2.87 (m, 11H), 2.26-2.15 (m, 3H), 1.93-189(m, 2H), 1.60-1.48 (m, 3H), 0.80-0.69 (m, 1H), 0.50-0.40 (m, 1H),0.35-0.33 (m, 2H), 0.07-0.02 (m, 2H); MS (ESI) m/z 570.0 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.03 (d, J=5.6 Hz, 1H), 4.41 (s, 2H), 4.09 (s,1H), 3.79-3.66 (m, 1H), 3.61-3.52 (m, 1H), 3.46-3.37 (m, 2H), 3.26-2.93(m, 10H), 2.43-2.33 (m, 1H), 2.27-2.20 (m, 1H), 2.18-2.05 (m, 2H),1.95-1.72 (m, 2H), 1.72-1.60 (m, 1H); MS (ESI) m/z 548.14 (M+H).

¹H NMR (400 MHz, CD₃(D) δ 6.98 (d, J=5.6 Hz, 1H), 4.26 (s, 2H), 4.00 (s,1H), 3.47-3.44 (m, 2H), 3.15-2.89 (m, 11H), 2.32-2.25 (m, 1H), 2.17-2.14(m, 1H), 1.95-1.92 (m, 3H), 1.76-1.66 (m, 2H), 1.64-1.02 (m, 10H); MS(ESI) m/z 598.1 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.05 (d, J=5.9 Hz, 1H), 4.31 (s, 2H), 4.09 (s,1H), 3.95-3.85 (m, 2H), 3.75 (t, J=7.3 Hz, 1H), 3.54 (dd, J=8.7, 5.5 Hz,1H), 3.20-2.90 (m, 11H), 2.70-2.59 (m, 1H), 2.40-2.30 (m, 1H), 2.28-2.13(m, 2H), 1.75-1.59 (m, 2H); MS (ESI) m/z 546.16 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.04 (d, J=5.9 Hz, 1H), 4.30 (s, 2H),4.18-3.94 (m, 4H), 3.90-3.80 (m, 1H), 3.80-3.65 (m, 1H), 3.24-2.85 (m,9H), 2.50-2.20 (m, 3H), 2.18-2.00 (m, 1H), 1.70-1.57 (m, 1H); MS (ESI)m/z 532.11 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.01 (d, J=5.9 Hz, 1H), 4.31 (d, J=5.0 Hz,2H), 4.23-4.15 (m, 1H), 4.08 (s, 1H), 3.95-3.88 (m, 1H), 3.85-3.78 (m,1H), 3.25-3.16 (m, 1H), 3.15-2.93 (m, 9H), 2.39-2.29 (m, 1H), 2.27-2.19(m, 1H), 2.17-2.07 (m, 1H), 2.00-1.91 (m, 2H), 1.70-1.56 (m, 2H); MS(ESI) m/z 546.13 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.05 (d, J=5.5 Hz, 1H), 4.28 (s, 2H), 4.10 (s,1H), 3.24-2.83 (m, 11H), 2.54-2.40 (m, 3H), 2.39-2.30 (m, 1H), 2.28-2.21(m, 1H), 2.11-1.90 (m, 5H), 1.70-1.50 (m, 2H), 1.23 (s, 3H), 1.01 (s,3H); MS (ESI) m/z 598.19 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.09 (d, J=6.0 Hz, 1H), 4.51 (d, J=1.7 Hz,2H), 4.09 (s, 1H), 3.78 (t, J=4.8 Hz, 2H) 3.46-3.40 (m, 5H), 3.24-2.94(m, 11H), 2.37 (t, J=14.7 Hz, 1H), 2.28-2.17 (m, 2H), 1.72-1.60 (m, 1H),1.09-1.01 (m, 6H); MS (ESI) m/z 576.24 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.09 (d, J=5.9 Hz, 1H), 4.55 (d, J=3.7 Hz,2H), 4.07 (s, 1H), 3.77 (t, J=4.8 Hz, 2H), 3.66-3.54 (m, 1H), 3.41 (s,3H), 3.48-3.37 (m, 1H), 3.25-2.90 (m, 11H), 2.43-2.33 (m, 1H), 2.28-2.20(m, 1H), 1.71-1.60 (m, 1H), 1.25-1.15 (m, 1H), 1.85-1.75 (m, 2H),0.50-0.42 (m, 2H); MS (ESI) m/z 574.21 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.14 (d, J=6.0 Hz, 1H), 4.56 (br, 2H), 4.09(s, 1H), 3.80 (br, 2H), 3.55-3.46 (m, 2H), 3.42 (s, 3H), 3.44-3.39 (m,1H), 3.22-2.92 (m, 10H), 2.42-2.33 (m, 1H), 2.27-2.20 (m, 1H), 1.72-1.60(m, 1H), 1.09 (s, 9H); MS (ESI) m/z 590.21 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.08 (d, J=5.9 Hz, 1H), 4.64-4.52 (m, 1H),4.38-4.22 (m, 1H), 4.10 (s, 1H), 3.98-3.82 (m, 2H), 3.76 (t, J=7.3 Hz,1H), 3.55-3.45 (m, 1H), 3.27-2.88 (m, 14H), 2.85-2.73 (m, 1H), 2.42-2.32(m, 1H), 2.28-2.19 (m, 2H), 1.77-1.59 (m, 2H); MS (ESI) m/z 560.21(M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.08 (d, J=5.9 Hz, 1H), 4.55-4.39 (m, 2H),4.08 (s, 1H), 3.98-3.82 (m, 2H), 3.75 (t, J=7.3 Hz, 1H), 3.53-3.40 (m,1H), 3.36-2.92 (m, 13H), 2.80-2.71 (m, 1H), 2.43-2.33 (m, 1H), 2.28-2.18(m, 2H), 1.73-1.59 (m, 2H), 1.40 (t, J=7.3 Hz, 3H); MS (ESI) m/z 574.28(M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.08 (d, J=5.9 Hz, 1H), 4.60-4.40 (m, 2H),4.09 (s, 1H), 4.02-3.94 (m, 1H), 3.92-3.84 (m, 1H), 3.83-3.73 (m, 1H),3.52-3.43 (m, 1H), 3.36-2.92 (m, 13H), 2.83-2.71 (m, 1H), 2.43-2.34 (m,1H), 2.33-2.18 (m, 3H), 1.75-1.60 (m, 2H), 1.06 (dd, J=13.7, 6.9 Hz,6H); MS (ESI) m/z 602.30 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.09 (d, J=6.0 Hz, 1H), 4.60-4.42 (m, 1H),4.36-4.22 (m, 2H), 4.22-4.09 (m, 2H), 4.10 (s, 1H), 3.84 (dd, J=11.4,6.0 Hz, 1H), 3.78-3.67 (m, 1H), 3.24-3.17 (m, 1H), 3.17-2.92 (m, 8H),2.83 (s, 3H), 2.54-2.20 (m, 4H), 1.70-1.59 (m, 1H); MS (ESI) m/z 546.14(M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.08 (d, J=6.0 Hz, 1H), 4.48 (d, J=13.7 Hz,1H), 4.43-4.11 (m, 4H), 4.09 (s, 1H), 3.90-3.78 (m, 1H), 3.76-3.64 (m,1H), 3.40-3.27 (m, 2H), 3.24-3.18 (m, 1H), 3.17-2.92 (m, 8H), 2.50-2.20(m, 4H), 1.71-1.59 (m, 1H), 1.45-1.32 (m, 3H); MS (ESI) m/z 560.19(M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.06 (dd, J=11.9, 5.9 Hz, 1H), 4.63 (t, J=11.7Hz, 1H), 4.44-4.25 (m, 2H), 4.09 (s, 1H), 4.00-3.82 (m, 2H), 3.47-3.39(m, 1H), 3.25-2.87 (m, 11H), 2.42-2.31 (m, 1H), 2.27-2.10 (m, 2H),2.02-1.90 (m, 2H), 1.71-1.56 (m, 2H); MS (ESI) m/z 560.18 (M+H).

Example 2 Synthesis of Compounds Via Scheme 2

The following compounds were prepared according to Scheme 2.

Compound S1-7 (0.25 g, 0.56 mmol, 1.0 equiv) was dissolved in1,2-dichloroethane (4 mL). Neopentylamine (98 mg, 0.11 mmol, 2.0 equiv)was added via a syringe, followed by the addition of acetic acid (64 μL,0.11 mmol) under a nitrogen atmosphere. After stirring at rt for 1 h,sodium triacetoxyborohydride (0.36 g, 1.68 mmol, 3.0 equiv) was added tothe reaction mixture. LC/MS indicated that the starting material wasconsumed after overnight. The reaction mixture was diluted withdichloromethane, washed with saturated aqueous NaHCO₃ (3×20 mL) andbrine, dried over sodium sulfate, filtered, and concentrated underreduced pressure to give the crude product, which was purified by columnchromatography (Biotage 10 g column, 10% to 20% EtOAc in hexanesgradient), yielding pure compound S2-1-1 as a colorless oil (0.25 g,86%): ¹H NMR (400 MHz, CDCl₃) δ 7.52-7.47 (m, 2H), 7.40-7.33 (m, 6H),7.25 (t, J=6.9 Hz, 1H), 7.04 (d, J=8.2 Hz, 2H), 5.10 (s, 2H), 4.04 (d,J=2.3 Hz, 2H), 2.35 (d, J=1.8 Hz, 3H), 2.30 (s, 2H), 0.89 (s, 9H).

LDA/THF was prepared by adding n-BuLi (0.29 mL, 1.6 M/hexanes, 0.46mmol, 3.0 equiv) to diisopropylamine (65 μL, 0.46 mmol, 3.0 equiv) in 3mL dry THF under a nitrogen atmosphere in a flame dried schenck flask at−78° C. The resulting solution was warmed to −20° C. and stirred foranother 15 min. After the LDA solution was cooled down to −78° C., TMEDA(69 μL, 0.46 mmol, 3.0 equiv) was added slowly via a syringe. CompoundS2-1-1 (0.10 g, 0.20 mmol, 1.3 equiv) was dissolved in I mL dry THF andadded into the LDA solution slowly via a syringe. A dark-red colorappeared as soon as addition started. After stirring for 10 min, enoneS1-9 (74 mg, 0.15 mmol, 1.0 equiv) in 1 mL dry THF was added slowly avia syringe. After 10 min, LC/MS indicated that the enone was consumedand the product present. The reaction mixture was allowed to slowly warmto −20° C. in 1 h. A phosphate buffer solution (pH 7, 10 m L) was added,followed by the addition of 20 mL saturated aqueous ammonium chloride.The resulting mixture was extracted with dichloromethane (3×15 mL). Thecombined extracts were dried over sodium sulfate, filtered andconcentrated under reduced pressure. The resulting orange-red oil waspurified by column chromatography (Biotage 10 g column, 10% to 30% EtOAcin hexanes gradient) to yield the desired compound S2-2-1 (90 mg, 65%).

Aqueous HF (0.3 mL, 48-50%) was added to a CH₃CN solution (1.0 mL) of 7(20 mg) in a plastic vial at 25° C. The reaction was stirred at 25° C.for 18 hrs. The resulting mixture was poured into an aqueous solution(10 mL) of K₂HPO₄ (2 g) The solution was extracted with EtOAc (3×15 mL).The combined EtOAc extracts were dried over sodium sulfate andconcentrated to give the crude intermediate.

10% Pd—C (5 mg) was added to a MeOH solution (2 mL) of the above crudeintermediate. HCl/MeOH (0.5 mL, 0.5 N) was also added. The reactionmixture was stirred under H₂ (balloon) at 25° C. for 2 hrs and filteredthrough a pad of Celite. The filtrate was concentrated to give the crudeproduct. The crude product was purified by HPLC on a Polymerx 10μ RP-γ100 R column [30×21.20 mm, 10 micron, solvent A: 0.05 N HCl, solvent B:CH₃CN, sample in 2.0 mL (0.05 N HCl), gradient elution with 0→70% B over15 min, mass-directed fraction collection] to yield the desired productS2-4-1 as a yellow solid (8 mg, 66%, 2 steps): ¹H NMR (400 MHz, CD₃OD) δ7.09 (d, J=6.0 Hz, 1H), 4.42 (s, 2H), 4.14 (s, 1H) 3.21 (dd, J=15.5, 4.6Hz, 1H), 3.05 (s, 3H), 2.97 (s, 3H), 2.92 (s, 2H), 3.17-2.97 (m, 2H),2.39-2.22 (m, 2H), 1.70-1.58 (m, 1H), 1.06 (s, 9H); MS (ESI) m/z 532.49(M+H).

The following compounds were prepared according to the methods forS2-4-1, substituting the appropriate amine for isobutylamine.

S2-4-2:

¹H NMR (400 MHz, CD₃OD/DCl) δ 7.08 (d, J=5.96 Hz, 1H), 4.27 (s, 2H),4.16 (s, 1H), 3.51 (hept, J=6.9 Hz, 1H), 3.28-2.94 (m, 9H), 2.38-2.26(m, 2H), 1.60 (dd, J=13.3, 11.0 Hz, 1H), 1.41 (d, J=6.9 Hz, 6H); MS(ESI) m/z 504.28 (M+H).

S2-4-3:

¹H NMR (400 MHz, CD₃OD/DCl) δ 7.09 (d, J=5.92 Hz, 1H), 4.22 (s, 2H),4.16 (s, 1H), 3.28-2.94 (m, 9H), 2.38-2.26 (m, 2H), 1.60 (dd, J=14.0,11.0 Hz, 1H), 1.47 (s, 9H); MS (ESI) m/z 518.28 (M+H).

S2-4-4:

¹H NMR (400 MHz, CD₃OD/DCl) δ 7.07 (d, J=5.96 Hz, 1H), 4.26 (s, 2H),4.16 (s, 1H), 3.66 (quint, J=6.9 Hz, 1H), 3.34-2.94 (m, 11H), 2.36-2.24(m, 2H), 2.23-2.12 (m, 2H), 1.90-1.54 (m, 5H); MS (ESI) m/z 530.23(M+H).

S2-4-5:

¹H NMR (400 MHz, CD₃OD/DCl) δ 7.08 (d, J=5.96 Hz, 1H), 4.21 (s, 2H),4.15 (s, 1H), 3.26-2.96 (m, 9H), 2.36-2.24 (m, 2H), 1.82 (q, J=7.32 Hz,2H), 1.69-1.55 (m, 1H), 1.42 (s, 6H), 1.02 (d, J=7.32 Hz, 3H); MS (ESI)m/z 532.24 (M+H).

S2-4-6:

¹H NMR (400 MHz, CD₃OD/DCl) δ 7.11 (d, J=5.96 Hz, 1H), 4.33 (s, 2H),4.16 (s, 1H), 3.26-2.94 (m, 9H), 2.36-2.25 (m, 2H), 1.69-1.55 (m, 1H),1.33 (s, 6H), 1.29-1.20 (m, 1H), 0.72-0.64 (m, 2H), 0.63-0.56 (m, 2H);MS (ESI) m/z 544.24 (M+H).

S2-4-7:

¹H NMR (400 MHz, CD₃OD/DCl) δ 7.11 (d, J=5.48 Hz, 1H), 4.24 (s, 2H),4.18 (s, 1H), 3.28-2.96 (m, 9H), 2.37-2.26 (m, 2H), 1.84 (s, 2H),1.69-1.54 (m, 7H), 1.10 (s, 9H); MS (ESI) m/z 574.28 (M+H).

S2-4-8:

¹H NMR (400 MHz, CD₃OD/DCl) δ 7.15 (d, J=5.96 Hz, 1H), 4.37 (s, 2H),4.17 (s, 1H), 3.56-3.48 (m, 2H), 3.40-2.94 (m, i 1H), 2.38-2.26 (m, 2H),1.99-1.78 (m, 5H), 1.70-1.48 (m, 2H); MS (ESI) m/z 530.29 (M+H).

S2-4-9:

¹H NMR (400 MHz, CD₃OD/DCl) δ 7.17 (d, J=5.96 Hz, 1H), 4.45 (s, 2H),4.16 (s, 1H), 4.08-3.98 (m, 2H), 3.92-3.80 (m, 2H), 3.52-3.42 (m, 2H),3.38-2.94 (m, 11H), 2.38-2.25 (m, 2H), 1.70-1.55 (m, 1H); MS (ESI) m/z532.27 (M+H).

S2-4-10:

¹H NMR (400 MHz, CD₃OD/DCl) δ 4.69 (s, 2H), 4.17 (s, 1H), 4.10-3.98 (m,2H), 3.95-3.84 (m, 2H), 3.34-2.94 (m, 13H), 2.38-2.25 (m, 2H), 1.71-1.57(m, 1H); MS (ESI) m/z 610.2, 612.19 (M+H).

S2-4-11:

¹H NMR (400 MHz, CD₃OD/DCl) δ 7.15 (br s, 1H), 4.76-4.58 (m, 2H), 4.17(s, 1H), 3.40-2.92 (m, 11H), 2.60-2.48 (m, 1H), 2.38-2.15 (m, 3H),1.99-1.82 (m, 2H), 1.82-1.55 (m, 2H), 1.45-1.36 (m, 1H), 1.22-1.14 (m,1H), 1.10-0.99 (m, 1H), 0.99-0.80 (m, 2H); MS (ESI) m/z 556.20 (M+H).

S2-4-12:

¹H NMR (400 MHz, CD₃OD/DCl) δ 7.12 (d, J=5.96 Hz, 1H), 4.56 (d, J=3.2Hz, 1H), 4.17 (s, 1H), 4.10 (d, J=3.2 Hz, 1H), 3.54-3.45 (m, 2H),3.26-2.96 (m, 9H), 2.39-2.26 (m, 2H), 2.23-1.95 (m, 4H), 1.70-1.56 (m,4H), 1.44 (s, 3H); MS (ESI) m/z 544.22 (M+H).

S2-4-13:

¹H NMR (400 MHz, CD₃OD) δ 7.08 (d, J=6.0 Hz, 1H), 4.42 (s, 2H), 4.14 (s,1H), 3.06 (s, 3H), 2.98 (s, 3H), 2.92 (s, 6H), 3.24-2.97 (m, 3H),2.37-2.25 (m, 2H), 1.70-1.57 (m, 1H); MS (ESI) m/z 490.43 (M+H).

S2-4-14:

¹H NMR (400 MHz, CD₃OD) δ 7.08 (d, J=6.0 Hz, 1H), 4.28 (s, 2H), 4.14 (s,1H), 3.21 (dd, J=15.5, 4.6 Hz, 1H), 3.06 (s, 3H), 2.97 (s, 3H), 2.94 (d,J=6.9 Hz, 2H), 3.17-2.97 (m, 2H), 2.35-2.25 (m, 2H), 2.12-2.02 (m, 1H),1.70-1.58 (m, 1H), 1.04 (d, J=6.9 Hz, 6H); MS (ESI) m/z 518.47 (M+H).

S2-4-15:

¹H NMR (400 MHz, CD₃OD) δ 7.03 (d, J=6.0 Hz, 1H), 4.28 (s, 2H), 4.12 (s,1H), 3.21 (dd, J=15.1, 4.6 Hz, 1H), 3.05 (s, 3H), 2.97 (s, 3H), 2.94 (d,J=6.9 Hz, 2H), 3.16-2.98 (m, 4H), 2.38-2.22 (m, 2H), 1.72-1.58 (m, 4H),0.97 (d, J=6.4 Hz, 6H); MS (ESI) m/z 532.50 (M+H).

S2-4-16:

¹H NMR (400 MHz, CD₃OD) δ 7.10 (d, J=5.5 Hz, 1H), 4.37 (s, 2H), 4.10 (s,1H), 3.50 (m, 1H), 3.27-2.93 (m, 5H), 3.05 (s, 3H), 2.97 (s, 3H), 2.85(m, 1H), 2.36 (t, J=15.1 Hz, 1H), 2.29-2.21 (m, 1H), 1.99-1.81 (m, 2H),1.72-1.53 (m, 2H), 1.49-1.38 (m, 1H), 1.12 (s, 3H), 1.02 (s, 3H); MS(ESI) m/z 558.49 (M+H).

S2-4-17:

¹H NMR (400 MHz, CD₃OD) δ 7.01 (d, J=6.0 Hz, 1H), 4.17 (s, 2H), 4.10 (s,1H), 3.21 (dd, J=15.1, 4.6 Hz, 1H), 3.05 (s, 3H), 2.97 (s, 3H), 2.84 (s,3H), 3.14-2.98 (m, 2H), 2.21-2.39 (m, 2H), 1.70-1.60 (m, 1H); MS (ESI)m/z 476.31 (M+H).

S2-4-18:

¹H NMR (400 MHz, CD₃OD) δ 7.00 (d, J=6.0 Hz, 1H), 4.14 (s, 2H), 4.10 (s,1H), 3.84 (m, 1H), 3.21 (dd, J=15.5, 4.6 Hz, 1H), 3.04 (s, 3H), 2.96 (s,3H), 3.14-2.97 (m, 2H), 2.36 (t, J=14.7 Hz, 1H), 2.40-2.30 (m, 3H),2.28-2.17 (m, 3H), 1.93 (m, 2H), 1.68-1.58 (m, 1H); MS (ESI) m/z 516.34(M+H).

S2-4-19:

¹H NMR (400 MHz, CD₃OD) δ 7.10 (d, J=5.5 Hz, 1H), 4.35 (s, 2H), 4.12 (s,1H), 3.51 (m, 2H), 3.24-2.98 (m, 5H), 3.05 (s, 3H), 2.97 (s, 3H), 2.34(t, J=15.1 Hz, 1H), 2.29-2.21 (m, 1H), 1.96-1.85 (m, 2H), 1.79-1.56 (m,2H), 1.54-1.40 (m, 2H), 0.99 (d, J=6.4 Hz, 3H); MS (ESI) m/z 544.25(M+H).

S2-4-20:

¹H NMR (400 MHz, CD₃OD) δ 7.07 (d, J=5.5 Hz, 1H), 4.39 (s, 2H), 4.09 (s,1H), 3.38 (m, 2H), 3.24-2.98 (m, 5H), 3.04 (s, 3H), 2.96 (s, 3H), 2.35(t, J=15.1 Hz, 1H), 2.27-2.19 (m, 1H), 1.77-1.58 (m, 5H), 1.09 (s, 3H),1.03 (s, 3H); MS (ESI) m/z 558.29 (M+H).

Compound S2-2-1 (30 mg, 0.033 mmol) was dissolved in 1,2-dichloroethane(2 mL). Formaldehyde solution (12 μL, 0.16 mmol, 5.0 equiv) and aceticacid (9 μL, 0.17 mmol) were added via a syringe under a nitrogenatmosphere. After stirring at rt for 1 h, sodium triacetoxyborohydride(21 mg, 0.16 mmol) was added to the reaction mixture. LC/MS indicatedthat the starting material was consumed after 2 hrs. The reactionmixture was diluted with dichloromethane, washed with NaHCO₃ (saturatedaqueous solution, 3×20 mL) and brine, dried over sodium sulfate,filtered, and concentrated under reduced pressure, yielding 26 mg ofcrude compound S2-2-2, which was used without further purification.

Aqueous HF (0.3 mL, 48-50%) solution was added to a CH₃CN solution (1.0mL) of S2-2-2 (crude, 26 mg) in a plastic vial at 25° C. The reactionwas stirred at 25° C. for 18 hrs. The resulting mixture was poured intoan aqueous solution (10 mL) of K₂HPO₄ (2 g). The solution was extractedwith EtOAc (3×15 mL). The combined EtOAc extracts were dried over sodiumsulfate and concentrated to give the crude intermediate.

Pd—C (5 mg, 10 wt %) was added to MeOH solution (2 mL) of the crudeintermediate. HCl in MeOH (0.5 N, 0.5 mL) was added. The reaction wasstirred under H₂ (balloon) at 25° C. for 2 hrs and filtered through apad of Celite. The filtrate was concentrated, and the crude product waspurified by HPLC on a Polymerx 10μ RP-γ 100 R column [30×21.20 mm, 10micron, solvent A: 0.05 N HCl, solvent B: CH₃CN, sample in 2.0 mL (0.05N HCl), gradient elution with 0→70% B over 15 min, mass-directedfraction collection]. Fractions containing the desired product werecollected and freeze-dried, yielding product S2-4-21 as a yellow solid19 mg (>95% for 3 steps): ¹H NMR (400 MHz, CD₃OD) δ 7.12 (d, J=5.8 Hz,1H), 4.58 (d, J=13.3 Hz, 1H), 4.36 (d, J=13.3 Hz, 1H), 4.11 (s, 1H),3.05 (s, 3H), 2.97 (s, 3H), 2.95 (s, 5H), 3.26-3.01 (m, 3H), 2.37 (t,J=14.6 Hz, 1H), 2.29-2.22 (m, 1H), 1.71-1.61 (m, 1H), 1.08 (s, 9H); MS(ESI) m/z 546.37 (M+H).

The following compounds were prepared according to the methods forS2-4-21 above, using either formaldehyde or substituting the appropriatealdehyde for formaldehyde.

S2-4-22:

¹H NMR (400 MHz, CD₃OD/DCl) δ 7.13 (d, J=5.48 Hz, 1H), 4.60-4.48 (m,1H), 4.36-4.26 (m, 1H), 4.17 (s, 1H), 3.40-2.94 (m, 11H), 2.85 (s, 3H),2.38-2.26 (m, 2H), 1.78-1.56 (m, 4H), 1.00-0.92 (m, 6H); MS (ESI) m/z546.30 (M+H).

S2-4-23:

¹H NMR (400 MHz, CD₃OD/DCl) δ 7.11 (d, J=5.96 Hz, 1H), 4.63-4.52 (m,1H), 4.33-4.24 (m, 1H), 4.16 (s, 1H), 3.26-2.94 (m, 11H), 2.87 (s, 3H),2.38-2.26 (m, 3H), 1.70-1.56 (m, 1H), 1.10-1.02 (m, 6H); MS (ESI) m/z532.31 (M+H).

S2-4-24:

¹H NMR (400 MHz, CD₃OD/DCl) δ 7.13 (d, J=5.92 Hz, 1H), 4.60-4.50 (m,1H), 4.24-4.14 (m, 2H), 3.76-3.66 (m, 1H), 3.26-2.94 (m, 9H), 2.79 (s,3H), 2.40-2.26 (m, 2H), 1.70-1.58 (m, 1H), 1.50-1.40 (m, 6H); MS (ESI)m/z 518.31 (M+H).

S2-4-25:

¹H NMR (400 MHz, CD₃OD/DCl) 7.10 (d, J=4.1 Hz, 1H), 4.80-4.72 (m, 1H),4.15 (s, 1H), 4.04-3.96 (m, 1H), 3.26-2.94 (m, 9H), 2.78-2.74 (m, 3H),2.39-2.25 (m, 2H), 1.72-1.53 (m, 10H); MS (ESI) m/z 532.30 (M+H).

S2-4-26:

¹H NMR (400 MHz, CD₃OD/DCl) δ 7.13 (d, J=5.5 Hz, 1H), 4.64-4.46 (m, 2H),4.17 (s, 1H), 3.26-2.94 (m, 12H), 2.39-2.25 (m, 2H), 1.70-1.56 (m, 1H),1.14-1.04 (m, 1H), 0.98-0.85 (m, 4H); MS (ESI) m/z 516.22 (M+H).

S2-4-27:

¹H NMR (400 MHz, CD₃OD/DCl) δ 7.12 (d, J=5.5 Hz, 1H), 4.62-4.53 (m, 1H),4.28-4.20 (m, 1H), 4.17 (s, 1H), 3.84-3.74 (m, 1H), 3.26-2.94 (m, 9H),2.79 (s, 3H), 2.39-2.25 (m, 3H), 2.23-2.13 (m, 1H), 1.97-1.81 (m, 4H),1.80-1.55 (m, 3H); MS (ESI) m/z 544.27 (M+H).

S2-4-28:

¹H NMR (400 MHz, CD₃OD/DCl) δ 7.10 (d, J=5.96 Hz, 1H), 4.80-4.71 (m,1H), 4.18 (s, 1H), 4.06-3.98 (m, 1H), 3.26-2.95 (m, 9H), 2.76 (s, 3H),2.37-2.25 (m, 2H), 2.01-1.89 (m, 2H), 1.69-1.54 (m, 1H), 1.51 (s, 3H),1.48 (s, 3H), 1.07 (t, J=6.4 Hz, 3H); MS (ESI) m/z 546.27 (M+H).

S2-4-29:

¹H NMR (400 MHz, CD₃OD/DCl) δ 7.11 (d, J=5.0 Hz, 1H), 4.96-4.88 (m, 1H),4.16 (s, 1H), 4.10-4.01 (m, 1H), 3.26-2.95 (m, 9H), 2.82 (s, 3H),2.39-2.25 (m, 2H), 1.70-1.58 (m, 1H), 1.50-1.28 (m, 7H), 0.82-0.59 (m,4H); MS (ESI) m/z 558.28 (M+H).

S2-4-30:

¹H NMR (400 MHz, CD₃OD/DCl) δ 7.10 (d, J=5.5 Hz, 1H), 4.82-4.74 (m, 1H),4.17 (s, 1H), 4.05-3.97 (m, 1H), 3.28-2.95 (m, 9H), 2.76 (s, 3H),2.38-2.26 (m, 2H), 2.01-1.80 (m, 2H), 1.76-1.56 (m, 7H), 1.12 (s, 9H);MS (ESI) m/z 588.29 (M+H).

S2-4-31:

¹H NMR (400 MHz, CD₃OD/DCl) δ 7.21 (d, J=5.0 Hz, 1H), 4.70-4.61 (m, 1H),4.32-4.26 (m, 1H), 4.19 (s, 1H), 3.56-3.45 (m, 1H), 3.34-2.95 (m, 10H),2.40-2.26 (m, 2H), 1.72-1.55 (m, 10H), 1.19 (t, J=7.3 Hz, 3H); MS (ESI)m/z 546.26 (M+H).

S2-4-32:

¹H NMR (400 MHz, CD₃OD/DCl) δ 7.12 (d, J=4.1 Hz, 1H), 4.51-4.34 (m, 2H),4.16 (s, 1H), 3.92-3.82 (m, 1H), 3.34-2.94 (m, 11H), 2.40-2.08 (m, 4H),1.98-1.79 (m, 4H), 1.78-1.55 (m, 3H), 1.36 (t, J=7.4 Hz, 3H); MS (ESI)m/z 558.29 (M+H).

S2-4-33:

¹H NMR (400 MHz, CD₃OD/DCl) δ 7.19 (d, J=5.5 Hz, 1H), 4.72-4.63 (m, 1H),4.34-4.24 (m, 1H), 4.17 (s, 1H), 3.59-3.50 ((m, 1H)), 3.26-2.96 (m,10H), 2.40-2.26 (m, 2H), 2.04-1.93 (m, 2H), 1.70-1.50 (m, 7H), 1.18 (t,J=7.3 Hz, 3H), 1.06 (t, J=7.6 Hz, 3H); MS (ESI) m/n 560.35 (M+H).

S2-4-34:

¹H NMR (400 MHz, CD₃OD/DCl) δ 7.15 (d, J=5.5 Hz, 1H), 4.64-4.44 (m, 2H),4.16 (s, 1H), 3.26-2.94 (m, 1H), 2.93-2.82 (m, 1H), 2.41-2.25 (m, 3H),1.70-1.56 (m, 1H), 1.20-1.05 (m, 7H), 1.05-0.84 (m, 3H); MS (ESI) m/z558.27 (M+H).

S2-4-35:

¹H NMR (400 MHz, CD₃OD/DCl) δ 7.20 (d, J=3.2 Hz, 1H), 4.60-4.49 (m, 2H),4.16 (s, 1H), 3.45-3.36 (m, 1H), 3.34-2.94 (m, 12H), 2.40-2.26 (m, 2H),1.70-1.56 (m, 1H), 1.36-1.26 (m, 1H), 1.07 (s, 9H), 0.86-0.74 (m, 2H),0.57-0.49 (m, 2H); MS (ESI) m/z 586.33 (M+H)

S2-4-36:

¹H NMR (400 MHz, CD₃OD/DCl) δ 7.13 (d, J=5.5 Hz, 1H), 4.54-4.33 (m, 2H),4.16 (s, 1H), 3.98-3.86 (m, 1H), 3.26-2.94 (m, 11H), 2.40-2.24 (m, 2H),1.70-1.56 (m, 1H), 1.52-1.35 (m, 6H), 1.20-1.08 (m, 1H), 0.80-0.70 (m,2H), 0.50-0.40 (m, 2H); MS (ESI) m/z 558.21 (M+H).

S2-4-37:

¹H NMR (400 MHz, CD₃OD/DCl) δ 7.18 (d, J=5.96 Hz, 1H), 4.52-4.35 (m,2H), 4.17 (s, 1H), 3.82-3.70 (m, 1H), 3.26-2.94 (m, 11H), 2.41-2.28 (m,2H), 2.04-1.93 (m, 1H), 1.71-1.58 (m, 1H), 1.52-1.38 (m, 6H), 1.08-1.02(d, J=6.9 Hz, 3H), 1.00-0.94 (d, J=6.4 Hz, 3H); MS (ESI) m/z 560.20(M+H).

S2-4-38:

¹H NMR (400 MHz, CD₃OD/DCl) δ 7.11 (d, J=5.5 Hz, 1H), 4.54-4.44 (m, 1H),4.28-4.22 (m, 1H), 4.15 (s, 1H), 3.80-3.72 (m, 1H), 3.36-2.94 (m, 11H),2.40-2.26 (m, 2H), 1.88-1.54 (m, 3H), 1.50-1.38 (m, 6H), 1.03-0.94 (m,3H); MS (ESI) m/z 546.20 (M+H).

S2-4-39:

¹H NMR (400 MHz, CD₃OD/DCl) δ 7.17 (d, J=5.5 Hz, 1H), 4.52-4.33 (m, 2H),4.17 (s, 1H), 3.84-3.72 (m, 1H), 3.36-2.94 (m, 11H), 2.40-2.16 (m, 3H),1.99-1.83 (m, 2H), 1.75-1.53 (m, 5H), 1.52-1.42 (m, 6H), 1.34-1.15 (m,2H); MS (ESI) m/z 586.26 (M+H).

S2-4-40:

¹H NMR (400 MHz, CD₃OD/DCl) δ 7.14 (d, J=5.5 Hz, 1H), 4.56-4.47 (m, 1H),4.33-4.24 (m, 1H), 4.17 (s, 1H), 3.84-3.72 (m, 1H), 3.36-2.94 (m, 11H),2.40-2.25 (m, 2H), 1.75-1.54 (m, 4H), 1.52-1.40 (m, 6H), 1.02-0.88 (m,6H); MS (ESI) m/z 574.26 (M+H).

S2-4-41:

¹H NMR (400 MHz, CD₃OD) δ 7.10 (d, J=5.9 Hz, 1H), 4.64 (br, s, 1H), 4.57(br, s, 1H), 4.10 (s, 1H), 3.21 (dd, J=15.1, 4.6 Hz, 1H), 3.05 (s, 3H),2.97 (s, 3H), 3.15-2.89 (m, 5H), 2.36 (m, 1H), 2.29-2.21 (m, 1H),1.70-1.60 (m, 1H), 133-1.23 (m, 1H), 1.10-0.85 (m, 3H), 0.85-0.79 (m,2H), 0.78-0.67 (m, 1H), 0.53-0.47 (m, 2H); MS (ESI) m/z 556.33 (M+H).

S2-4-42:

¹H NMR (400 MHz, CD₃OD) δ 7.10 (d, J=5.5 Hz, 1H), 4.54 (d, J=6.4 Hz,2H), 4.12 (s, 1H), 3.21 (dd, J=15.1, 4.6 Hz, 1H), 3.17-2.95 (m, 4H),3.05 (s, 3H), 2.97 (s, 3H), 2.92-2.87 (m, 1H), 2.36 (t, J=13.8 Hz, 1H),2.29-2.21 (m, 1H), 1.9-1.84 (m, 2H), 1.70-1.60 (m, 1H), 1.03 (t, J=7.3Hz, 3H), 1.10-0.85 (m, 3H), 0.82-0.68 (m, 1H); MS (ESI) in 544.33 (M+H).

S2-4-43:

¹H NMR (400 MHz, CD₃OD) δ 7.09 (d, J=5.5 Hz, 1H), 4.51 (d, J=13.3 Hz,1H), 4.39 (d, J=13.3 Hz, 1H), 4.07 (s, 1H), 3.03 (s, 3H), 2.95 (s, 3H),3.25-2.96 (m, 7H), 2.42-2.33 (m, 1H), 2.26-2.18 (m, 1H), 1.70-1.60 (m,1H), 1.43 (t, J=7.3 Hz, 3H), 1.06 (s, 9H); MS (ESI) m/z 560.50 (M+H).

S2-4-44:

¹H NMR (400 MHz, CD₃OD) δ 7.09 (d, J=5.5 Hz, 1H), 4.52 (d, J=13.3 Hz,1H), 4.41 (d, J=13.3 Hz, 1H), 4.07 (s, 1H), 3.03 (s, 3H), 2.96 (s, 3H),3.25-2.96 (m, 7H), 2.43-2.33 (m, 1H), 2.27-2.19 (m, 1H), 1.98-1.88 (m,1H), 1.86-1.74 (m, 1H), 1.71-1.61 (m, 1H), 1.08 (s, 9H), 1.01 (t, J=6.9Hz, 3H); MS (ESI) m/z 574.52 (M+H).

S2-4-45:

¹H NMR (400 MHz, CD₃OD) δ 7.08 (d, J=5.5 Hz, 1H), 4.53 (d, J=6.8 Hz,2H), 4.10 (s, 1H), 3.41 (q, J=7.3 Hz, 2H), 3.21 (dd, J=15.1, 4.6 Hz,1H), 3.17-2.95 (m, 2H), 3.04 (s, 3H), 2.96 (s, 3H), 2.93-2.85 (m, 1H),2.36 (t, J=13.8 Hz, 1H), 2.29-2.20 (m, 1H), 1.69-1.59 (m, 1H), 1.46 (t,J=7.3 Hz, 3H), 1.10-0.84 (m, 3H), 0.79-0.69 (m, 1H); MS (ESI) m/z 530.38(M+H).

S2-4-46:

¹H NMR (400 MHz, CD₃OD) δ 7.07 (d, J=5.9 Hz, 1H), 4.58 (d, J=13.3 Hz,1H), 4.26 (d, J=13.3 Hz, 1H), 4.10 (s, 1H), 3.05 (s, 3H), 2.97 (s, 3H),2.87 (s, 5H), 3.27-2.96 (m, 3H), 2.43-2.32 (m, 2H), 2.28-2.20 (m, 1H),2.03-1.91 (m, 2H), 1.78-1.60 (m, 5H), 1.36-1.20 (m, 2H); MS (ESI) m/z558.40 (M+H).

S-2-4-47:

¹H NMR (400 MHz, CD₃OD) δ 7.06 (d, J=5.9 Hz, 1H), 4.56 (d, 0.1=13.3 Hz,1H), 4.23 (d, J=13.3 Hz, 1H), 4.09 (s, 1H), 3.04 (s, 3H), 2.97 (s, 3H),2.86 (s, 5H), 3.27-2.96 (m, 3H), 2.37 (t, J=13.8 Hz, 1H), 2.28-2.20 (m,1H), 1.96-1.59 (m, 7H), 1.44-1.30 (m, 2H), 1.29-1.19 (m, 1H), 1.13-0.95(m, 2H); MS (ESI) m/z z 572.41 (M-+H).

S2-4-48:

¹H NMR (400 MHz, CD₃OD) δ 7.09 (d, J=5.5 Hz, 1H), 4.52 (d, J=13.3 Hz,1H), 4.41 (d, J=13.3 Hz, 1H), 4.07 (s, 1H), 3.03 (s, 3H), 2.96 (s, 3H),3.25-2.96 (m, 6H), 2.43-2.33 (m, 1H), 2.27-2.19 (m, 1H), 1.66 (m, 1H),1.08 (s, 9H), 1.10-0.85 (m, 3H), 0.81-0.71 (m, 1H); MS (ESI) m/z 572.43(M+H).

S2-4-49:

¹H NMR (400 MHz, CD₃OD) δ 7.08 (d, J=6.0 Hz, 1H), 4.50 (d, J=13.7 Hz,1H), 4.37 (d, J=13.7 Hz, 1H), 4.28 (s, 2H), 4.10 (s, 1H), 3.21 (dd,J=15.5, 4.6 Hz, 1H), 3.05 (s, 3H), 2.97 (s, 3H), 3.17-2.98 (m, 6H), 2.37(t, J=14.7 Hz, 1H), 2.29-2.12 (m, 2H), 1.93-1.73 (m, 2H), 1.71-1.61 (m,1H), 1.09-0.98 (m, 9H); MS (ESI) m/z 560.35 (M+H).

S-2-4-50:

¹H NMR (400 MHz, CD₃ OD) δ 7.08 (d, J=6.0 Hz, 1H), 4.50 (d, J=13.5 Hz,1H), 4.34 (d, J=13.5 Hz, 1H), 4.28 (s, 2H), 4.10 (s, 1H), 3.04 (s, 3H),2.96 (s, 3H), 3.27-2.97 (m, 7H), 2.36 (t, J=14.7 Hz, 1H), 2.28-2.12 (m,2H), 1.70-1.60 (m, 1H), 1.39 (t, J=6.9 Hz, 3H), 1.05 (dd, J=15.1, 6.4Hz, 6H); MS (ESI) m/z 546.39 (M+H).

S2-4-51:

¹H NMR (400 MHz, CD₃OD) δ 7.07 (d, J=6.0 Hz, 1H), 4.41 (d, J=12.4 Hz,1H), 4.14 (d, J=12.4 Hz, 1H), 4.12 (s, 1H), 3.88 (m, 1H), 3.05 (s, 3H),2.97 (s, 3H), 3.25-2.97 (m, 3H), 2.70 (s, 3H), 2.43-2.22 (m, 6H),1.96-1.77 (m, 2H), 1.69-1.59 (m, 1H); MS (ESI) m/z 530.34 (M+H).

S2-4-52:

¹H NMR (400 MHz, CD₃OD) δ 7.09 (d, J=6.0 Hz, 1H), 4.31 (br, s, 2H), 4.14(s, 1H), 4.00-3.92 (m, 1H), 3.06 (s, 3H), 2.97 (s, 3H), 3.26-2.97 (m,5H), 2.42-2.22 (m, 6H), 1.92-1.77 (m, 2H), 1.69-1.59 (m, 1H), 1.35 (t,J=6.8 Hz, 3H); MS (ESI) m/z 544.35 (M+H).

S2-4-53:

¹H NMR (400 MHz, CD₃OD) δ 7.11 (d, J=6.0 Hz, 1H), 4.48 (m, 1H), 4.37 (m,1H), 4.13 (s, 1H), 4.04 (m, 1H), 3.05 (s, 3H), 2.97 (s, 3H), 3.25-2.95(m, 5H), 2.45-2.13 (m, 6H), 1.89-1.74 (m, 2H), 1.69-1.59 (m, 1H),1.19-1.11 (m, 1H), 0.81-0.72 (m, 2H), 0.46-0.36 (m, 2H); MS (ESI) m/z570.39 (M+H).

S2-4-54:

¹H NMR (400 MHz, CD₃OD) δ 7.09 (d, J=5.0 Hz, 1H), 6.48 (t, J=53.6 Hz,1H), 4.55 (s, 2H), 4.11 (s, 1H), 3.83 (t, J=14.2 Hz, 2H), 3.05 (s, 3H),3.01 (s, 3H), 2.97 (s, 3H), 3.25-2.98 (m, 5H), 2.37 (t, J=14.7 Hz, 1H),2.29-2.21 (m, 1H), 1.70-1.60 (m, 1H); MS (ESI) m/z 540.31 (M+H).

S2-4-55:

¹H NMR (400 MHz, CD₃OD) δ 7.11 (br, s, 1H), 6.51 (t, J=53.6 Hz, 1H),4.64 (s, 2H), 4.12 (s, 1H), 3.87 (t, J=14.2 Hz, 2H), 3.05 (s, 3H), 2.97(s, 3H), 3.25-2.98 (m, 7H), 2.44-2.22 (m, 2H), 1.70-1.61 (m, 1H),1.27-1.19 (m, 1H), 0.88-0.80 (m, 2H), 0.55-0.45 (m, 2H); MS (ESI) m/z580.34 (M+H).

S2-4-56:

¹H NMR (400 MHz, CD₃OD) δ 7.07 (d, J=5.0 Hz, 1H), 6.38 (t, J=53.6 Hz,1H), 4.40 (br, s, 2H), 4.09 (s, 1H), 3.56 (m, 2H), 3.03 (s, 3H), 2.96(s, 3H), 3.22-2.98 (m, 5H), 2.35 (t, J=14.2 Hz, 1H), 2.28-2.08 (m, 2H),1.69-1.59 (m, 1H), 1.02 (d, J, =6.9 Hz, 6H); MS (ESI) m/z 582.34 (M+H).

S2-4-57:

¹H NMR (400 MHz, CD₃OD) δ 7.08 (t, J=6.0 Hz, 1H), 4.61 (dd, J=18.3, 13.7Hz, 1H), 4.18 (dd, J=78.3, 13.7 Hz, 1H), 4.10 (s, 1H), 3.87 (t, J=14.2Hz, 1H), 3.05 (s, 3H), 2.97 (s, 3H), 2.84 (s, 3H), 3.25-2.98 (m, 3H),2.42-2.20 (m, 3H), 1.70-1.60 (m, 1H), 1.41 (dd, J=30.2, 6.9 Hz, 3H),1.13 (dd, J=30.2, 6.9 Hz, 3H), 1.04 (dd, J:=15.6, 6.9 Hz, 3H); MS (ESI)m/z 546.30 (M+H).

S2-4-58:

¹H NMR (400 MHz, CD₃OD) δ 7.07 (m, 1H), 4.08 (s, 1H), 4.61 (dd, J=183,137 Hz, 1H), 4.18 (dd, J=78.3, 13.7 Hz, 1H), 3.47 (m, 1H), 3.03 (s, 3H),2.96 (s, 3H), 3.41-2.97 (m, 5H), 2.42-2.20 (m, 3H), 1.70-1.60 (m, 1H),1.37 (dd, J=30.2, 6.9 Hz, 3H), 1.29 (t, J=6.9 Hz, 3H), 1.13 (dd, J=30.2,6.9 Hz, 3H), 1.03 (dd, J=15.6, 6.9 Hz, 3H); MS (ESI) m/z 560.33 (M+H).

S2-4-59:

¹H NMR (400 MHz, CD₃OD) δ 7.08 (t, J=6.0 Hz, 1H), 4.61 (dd, J=18.3, 13.7Hz, 1H), 4.18 (dd, J=78.3, 13.7 Hz, 1H), 4.10 (s, 1H), 3.05 (s, 3H),2.97 (s, 3H), 3.27-2.98 (m, 4H), 2.83 (s, 3H), 2.42-2.20 (m, 3H),1.70-1.60 (m, 1H), 1.41 (dd, J=30.2, 6.9 Hz, 3H), 1.13 (dd, J=30.2, 6.9Hz, 3H), 1.04 (dd, J=15.6, 6.9 Hz, 3H); MS (ESI) m/z 546.32 (M+H).

S2-4-60:

¹H NMR (400 MHz, CD₃OD) δ 7.10 (d, J=5.9 Hz, 1H), 4.75 (d, J=13.3 Hz,1H), 4.60 (d, J==13.3, 1H), 4.10 (s, 1H), 3.04 (s, 3H), 3.02 (s, 3H),2.96 (s, 3H), 3.25-2.96 (m, 3H), 2.41-2-20 (m, 2H), 1.70-1.59 (m, 2H),1.19-1.01 (m, 2H), 0.96-0.88 (m, 1H), 0.86-0.70 (m, 3H), 0.43-031 (m,2H); MS (ESI) m/z 556.31 (M+H).

S2-4-61:

¹H NMR (400 MHz, CD₃OD) δ 7.10 (d, J=5.9 Hz, 1H), 4.75 (d, J=13.3 Hz,1H), 4.60 (d, J=13.3, 1H), 4.10 (s, 1H), 3.05 (s, 3H), 2.96 (s, 3H),3.25-2.96 (m, 5H), 2.41-2-20 (m, 2H), 1.70-1.59 (m, 2H), 1.35 (t, J=6.8Hz, 3H), 1.19-1.01 (m, 2H), 0.96-0.88 (m, 1H), 0.86-0.70 (m, 3H),0.43-0.31 (m, 2H); MS (ESI) m/z 570.32 (M+H).

S2-4-62:

¹H NMR (400 MHz, CD₃OD) δ 7.17 (d, J=6.0 Hz, 1H), 4.51-4.33 (m, 2H),4.17 (s, 1H), 3.27-3.19 (m, 1H), 3.08 (s, 3H), 2.99 (s, 3H), 3.17-2.97(m, 4H), 2.38-2.27 (m, 2H), 2.27-2.18 (m, 1H), 1.99-1.83 (m, 2H),1.74-1.55 (m, 5H), 1.43 (t, J=7.3 Hz, 3H), 1.32-1.14 (m, 2H); MS (ESI)m/z 572.39 (M+H).

S2-4-63:

¹H NMR (400 MHz, CD₃OD) δ 7.11-7.07 (m, 1H), 4.61 (dd, J=18.3, 13.7 Hz,1H), 4.29, 4.09 (ABq, J=13.7 Hz, 1H), 4.11 (s, 1H), 3.51-3.43 (m, 1H),3.03 (s, 3H), 2.96 (s, 3H), 3.41-2.97 (m, 5H), 2.34 (t, J=6.9 Hz, 1H),2.27-2.20 (m, 1H), 2.06-1.95 ((m, 1H)), 1.74-1.59 (m, 2H), 1.44 (d,J=6.1 Hz, 3H), 1.29 (t, J=6.9 Hz, 3H), 1.08 (t, J=7.6 Hz, 3H); MS (ESI)m/z 546.38 (M+H).

S2-4-64:

¹H NMR (400 MHz, CD₃OD) δ 7.11 (d, J=6.0 Hz, 1H), 4.80-4.71 (m, 1H),4.18 (s, 1H), 4.06-3.98 (m, 1H), 3.26-2.95 (m, 9H), 2.76 (s, 3H),2.42-2.30 (m, 2H), 2.01-1.89 (m, 1H), 1.69-1.54 (m, 1H), 1.51 (s, 3H),1.48 (s, 3H), 1.02 (d, J=6.4 Hz, 6H); MS (ESI) m/z 560.23 (M+H).

Compound S1-7 (89 mg, 0.20 mmol, 1.0 equiv) and (S)-2-methylpiperidine(60 μL, 0.50 mmol, 2.5 equiv) were dissolved in 1,2-dichloroethane (2mL). Titanium(IV) isopropoxide (0.18 mL, 0.60 mmol, 3.0 equiv) was addedat rt. After stirring at rt overnight, LC/M S indicated that most of thestarting material was consumed and the intermediate formed. MeOH (1 mL)and sodium borohydride (40 mg, 1.1 mmol, 5.5 equiv, added in 4 equalportions) were added until the intermediate was completely converted tothe product. The reaction mixture was diluted with dichloromethane,washed with saturated aqueous sodium bicarbonate, water (2×20 mL) andbrine, dried over sodium sulfate, filtered, and concentrated underreduced pressure. The crude product was purified by columnchromatography (Biotage 10 g column, 10% to 50% EtOAc in hexanesgradient), yielding 86 mg (82%) of the desired compound S2-1-3 as acolorless oil.

LDA was prepared by adding n-BuLi (0.24 mL, 1.6 M/hexanes, 0.38 mmol,3.0 equiv) to diisopropylamine (53 μL, 0.38 mmol, 3.0 equiv) in 2 mL dryTHF under a nitrogen atmosphere in a flame dried schenck flask cooled at−78° C. The resulting solution was warmed to −20° C. and stirred for 15min. After the LDA solution was cooled down to −78° C., TMEDA (57 μL,0.38 mmol, 3.0 equiv) was added slowly via a syringe, followed by thedropwise addition of compound S2-1-3 (86 mg, 0.16 mmol, 1.3 equiv) in 1mL dry THF (a dark-red color appeared as soon as addition started).After stirring for 10 min, enone S1-9 (54 mg, 0.13 mmol, 1.0 equiv) in 1mL dry THF was added slowly via a syringe. After 10 min, LC/MS indicatedthat the enone was consumed and the product present. The reactionmixture was allowed to slowly warm to −30° C. in 1 h, added with aphosphate buffer (pH 7, 10 mL) and saturated aqueous ammonium chloride(20 mL), and extracted with dichloromethane (3×15 mL) The combinedextracts were dried over sodium sulfate, filtered, and concentratedunder reduced pressure. The resulting orange-red oil was purified bypreparative reverse phase HPLC on a Waters Autopurification system usinga Sunfire Prep C18 OBD column [5 μm, 19×50 mm; flow rate, 20 mL/min;Solvent A: H₂O with 0.1% HCO₂H; Solvent B: CH₃CN with 0.1% HCO₂H;injection volume: 4.0 mL (CH₃CN); gradient: 20→100% B over 15 min;mass-directed fraction collection]. Fractions containing the desiredproduct were collected and concentrated at rt to remove most of theacetonitrile. The resulting mostly aqueous solution was extracted withEtOAc. The EtOAc extract was dried (sodium sulfate) and concentrated togive 26 mg (23%) of the desired compound S2-2-3: ¹H NMR (400 MHz, CDCl₃)δ 16.00 (br, s, 1H), 7.58-7.54 (m, 2H), 7.51-7.47 (m, 2H), 7.40-7.31 (m,6H), 5.35 (s, 2H), 4.98 (q, J=11.0 Hz, 2H), 4.13-4.07 (m, 1H), 3.93 (d,J=11.0 Hz, 1H), 3.42 (d, J=12.2 Hz, 1H), 3.24 (dd, J=15.9, 4.9 Hz, 1H),3.03-2.93 (m, 1H), 2.69-2.62 (m, 1H), 2.58-2.51 (m, 1H), 2.48 (s, 6H),2.50-2.40 (m, 3H), 2.19-2.10 (m, 2H), 1.66-1.58 (m, 2H), 1.48-1.26 (m,4H), 1.22 (d, J=6.1 Hz, 3H), 0.81 (s, 9H), 0.26 (s, 3H), 0.12 (s, 3H).

Aqueous HF (0.3 mL, 48-50%) was added to a CH₃CN solution (1.0 mL) ofS2-2-3 (26 mg) in a plastic vial at 25° C. The reaction was stirred at25° C. for 18 hrs. The resulting mixture was poured into an aqueoussolution (10 mL) of K₂H—PO₄ (2 g) The solution was extracted with EtOAc(3×15 mL). The combined EtOAc extracts were dried over sodium sulfateand concentrated to give the crude intermediate (18 mg).

Pd—C (10 mg, 10 wt %) was added to a MeOH solution (2 mL) of the abovecrude intermediate. HCl/MeOH (0.5 mL, 0.5 N) was also added. Thereaction was stirred under H₂ (balloon) at 25° C. for 2 hrs and filteredthrough a pad of Celite. The filtrate was concentrated, and the crudeproduct was purified by HPLC on a Polymerx 10μ RP-γ 100 R column[30×21.20 mm, 10 micron, solvent A: 0.05 N HCl, solvent B: CH₃CN, samplein 2.0 mL (0.05 N HCl), gradient elution with 0→70% B over 15 min,mass-directed fraction collection] to yield the desired product S2-4-65as a yellow solid (9 mg, 59%, two steps): ¹H NMR (400 MHz, CD₃OD) δ 7.07(d, J=6.0 Hz, 1H), 4.76 (d, J=13.7 Hz, 1H), 4.15 (d, J=13.7 Hz, 1H),4.10 (s, 1H), 3.40-3.32 (m, 2H), 3.05 (s, 3H), 2.97 (s, 3H), 3.27-2.96(m, 4H), 2.42-2.32 (m, 1H), 2.27-2.21 (m, 1H), 1.92-1.80 (m, 2H),1.73-1.58 (m, 3H), 1.56 (d, J=6.4 Hz, 3H); MS (ESI) m/z 544.26 (M+H).

The following compounds were prepared according to the methods ofS2-4-65, substituting the appropriate amine for 2-methylpiperidine.

S2-4-66:

¹H NMR (400 MHz, CD₃OD) δ 7.06 (dd, J=8.2, 6.0 Hz, 1H), 4.40 (s, 2H),4.09 (s, 1H), 3.68-3.57 (m, 2H), 3.24-2.98 (m, 3H), 3.04 (s, 3H), 2.96(s, 3H), 2.40-2.32 (m, 1H), 2.29-2.21 (m, 1H), 2.05-1.58 (m, 7H), 1.54(d, J=6.0 Hz, 3H), 1.35 (d, J=6.0 Hz, 3H); MS (ESI) m/z 558.31 (M+H).

S2-4-67:

¹H NMR (400 MHz, CD₃OD) δ 7.08 (d, J=6.0 Hz, 1H), 4.33 (s, 2H), 4.15(br, s, 2H), 4.09 (s, 1H), 3.04 (s, 3H), 2.97 (s, 3H), 3.23-2.96 (m,3H), 2.38-2.29 (m, 3H), 2.27-2.20 (m, 1H), 2.08-2.01 (m, 2H), 1.86-1.80(m, 2H), 1.71-1.61 (m, 1H); MS (ESI) m/z 542.26 (M+H).

Acetic anhydride (3.6 μL, 0.038 mmol, 2.0 equiv) was added to a solutionof S2-2-1 (17 mg, 0.019 mmol, 1.0 equiv) in dichloromethane (1 mL).After 2 hrs, the reaction mixture was concentrated under reducedpressure. The crude product was purified by preparative reverse phaseHPLC on a Waters Autopurification system using a Sunfire Prep C18 OBDcolumn [5 μm, 19×50 mm; flow rate, 20 mL/min; Solvent A: H₂O with 0.1%HCO₂H; Solvent B: CH₃CN with 0.1% HCO₂H; gradient: 90→100% B over 15min; mass-directed fraction collection]. Fractions containing thedesired product, eluting at 5.0-6.0 min, were collected and concentratedunder reduced pressure to give 12 mg (66%) of the desired compoundS2-2-4: ¹H NMR (400 MHz, CDCl₃) δ 16.02-15.88 (m, 1H), 7.58-7.44 (m,4H), 7.40-7.28 (m, 6H), 5.36 (s, 2H), 5.03-4.70 (m, 4H), 3.94 (hr s,1H), 3.30-3.14 (m, 3H), 3.04-2.93 (m, 1H), 2.64-2.32 (m, 9H), 2.16-2.06(m, 4H), 1.04-0.94 (m, 9H), 0.81 (s, 9H), 0.24 (s, 3H), 0.12 (s, 3H); MS(ESI) m/z 944.61, 946.61 (M+H).

A solution of compound S2-2-4 (12 mg, 0.013 mmol) in 1,4-dioxane (0.80mL) was treated with HF (0.40 mL, 48-50% aqueous solution) at rt. Afterstirring overnight, the mixture was poured into a solution of K₂HPO₄(4.8 g) in water (20 mL). This mixture was extracted with EtOAc (3times), and the combined extracts were dried over sodium sulfate,filtered, and concentrated under reduced pressure to yield the crudeintermediate.

The above crude intermediate was dissolved in MeOH (1 mL)/1,4-dioxane (1mL). HCl/MeOH (0.5 mL, 0.5 N) and 10% Pd—C (Degussa, 2 mg) were added,and an atmosphere of hydrogen was introduced. After 2 hrs, the reactionmixture was filtered through Celite and concentrated under reducedpressure. The crude product was purified by preparative reverse phaseHPLC on a Waters Autopurification system using a Polymerx 10μ RP-γ 100 Rcolumn [30×21.20 mm, 10 micron, solvent A: 0.05 N HCl, solvent B: CH₃CN,gradient elution with 0→70% B over 10 min; mass-directed fractioncollection]. Fractions containing the desired product, eluting at9.8-11.4 min, were collected and freeze-dried to yield the desiredcompound S2-4-68 (5 mg, 69%): ¹H NMR (400 MHz, CD₃OD/DCl) δ 7.14 (d,J=5.5 Hz, 1H), 4.40 (s, 2H), 4.15 (s, 1H), 3.82-3.56 (m, 5H), 3.26-2.94(m, 9H), 2.36-2.24 (m, 2H), 2.24-1.98 (br m, 9H), 1.70-1.55 (m, 1H); MS(ESI) m/z 574.33 (M+H).

Compound S2-1-2 was prepared from S1-7 using similar procedures to thatof S15-15-2. A colorless oil: ¹H NMR (400 MHz, CDCl₃) δ 7.49 (dd, J=2.3,7.8 Hz, 2H), 7.33-7.38 (m, 5H), 7.25 (t, J=7.8 Hz, 1H), 7.05 (d, J=7.8Hz, 2H), 5.10 (s, 2H), 3.81 (s, 2H), 3.43 (s, 3H), 2.93 (s, 3H), 2.34(s, 3H), 2.07 (s, 3H), 1.45 (s, 6H); MS (ESI) m/z 571.2 (M+H), calcd forC₂₉H₃₂BrFN₂O₄ 571.15.

Compound S2-4-69 was prepared from S2-1-2 using similar procedures tothat of S2-4-1. The crude product was purified by HPLC on a WatersAutopurification system using a Phenomenex Polymerx 10μ RP-γ 100 Rcolumn [30×21.20 mm, 10 micron; flow rate, 20 mL/min; Solvent A: 0.05 NHCl/water; Solvent B: MeOH; injection volume: 4.0 mL (0.05 N HCl/water);gradient: 10→100% B over 20 min; mass-directed fraction collection].Fractions containing the desired product, eluting at 10.20-10.80 min,were collected and freeze-dried to give the desired product S2-4-69 as ayellow solid: ¹H NMR (400 MHz, CD₃OD) δ 7.39 (d, J=5.8 Hz, 1H), 4.23 (d,J=12.4 Hz, 1H), 4.15 (d, J=12.4 Hz, 1H), 4.10 (s, 1H), 2.97-3.16 (m,15H), 2.71 (s, 3H), 2.35 (dd, J=15.1 Hz, 1H), 2.23-2.26 (m, 1H), 1.86(s, 3H), 1.66 (s, 3H), 1.60-1.70 (m, 1H); MS (ESI) m/z 589.5 (M+H),calcd for C₂₉H₃₈FN₄O₈ 589.26.

Example 3 Synthesis of Compounds Via Scheme 3

The following compounds were prepared according to Scheme 3.

Compound S1-7 (0.42 g, 0.94 mmol, 1.0 equiv) was dissolved in MeOH (5mL) Sodium borohydride (76 mg, 2.00 mmol, 2.1 equiv) was added inseveral portions. During the addition, gas evolution was observed. Afterstirring at rt for 30 min, LC/MS indicated that the starting materialwas consumed. The reaction mixture was diluted with EtOAc, washed withwater (2×20 mL) and brine, dried over sodium sulfate, filtered, andconcentrated under reduced pressure. The crude material was purified bycolumn chromatography (Biotage 10 g column, 50% to 20% EtOAc in hexanesgradient), yielding 0.37 g (88%) of the desired compound S3-1 as acolorless oil: ¹H NMR (400 MHz, CDCl₃) δ 10.37 (s, 1H), 7.49 (dd, J=7.8,2.3 Hz, 2H), 7.40-7.33 (m, 5H), 7.25 (t, J=7.8 Hz, 1H), 7.07-7.02 (m,2H), 5.10 (s, 2H), 4.91 (dd, J=6.9, 2.3 Hz, 2H), 2.35 (d, J=2.3 Hz, 3H).

LDA was freshly prepared by adding n-BuLi (1.6 M/hexanes, 1.59 mmol, 3.0equiv) to diisopropylamine (0.22 mL, 1.59 mmol, 3.0 equiv) in 10 mL, dryTHF under a nitrogen atmosphere in a flame dried schenck flask at −78°C. The pale solution was warmed to −20° C. and stirred for 15 min. Afterthe LDA solution was cooled down to −78° C. with a dry ice/acetone bath,TMEDA (0.24 mL, 1.59 mmol, 3.0 equiv) was added slowly via a syringe.Compound S3-1 (0.28 g, 0.64 mmol, 1.2 equiv) in 2 mL dry THF was addedto slowly via a syringe. A dark-red color appeared as soon as theaddition started. After stirring at −78° C. for 10 min, enone S1-9 (0.26g, 0.53 mmol, 1.0 equiv) 2 mL, dry THF was added slowly via a syringe.After 10 min, LC/MS indicated that the enone was consumed and theproduct present. The reaction mixture was allowed to slowly warm to −20°C. in 1 h. Phosphate buffer (pH 7, 10 mL) was added, followed by theaddition of 20 mL saturated aqueous ammonium chloride. The resultingmixture was extract with dichloromethane (3×15 mL.). The combinedextracts were dried over sodium sulfate, filtered, and concentratedunder reduced pressure. The resulting orange-red oil was purified bycolumn chromatography (Biotage 24 g column, 10% to 30% EtOAc in hexanesgradient) yielding 0.22 g of compound S3-2 (50%): ¹H NMR (400 MHz,CDCl₃) δ 16.1 (br, s, 1H), 7.58-7.54 (m, 2H), 7.51-7.47 (m, 2H),7.41-7.32 (m, 6H), 5.36 (s, 2H), 4.95 (dd, J=26.6, 9.6 Hz, 2H), 4.89 (d,J=7.8 Hz, 2H), 3.92 (d, J=10.6 Hz, 1H), 3.25 (dd, J=15.6, 4.1 Hz, 1H),3.04-2.94 (m, 1H), 2.59-2.53 (m, 1H), 2.49 (s, 6H), 2.40 (t, J=15.6 Hz,1H), 2.20-2.10 (m, 2H), 0.81 (s, 9H), 0.26 (s, 3H), 0.12 (s, 3H).

Aqueous HF (0.3 mL, 48-50%) solution was added to a CH₃CN solution (1.0mL) of S3-2 (5 mg, 0.06 mmol) in a plastic vial at 25° C. The reactionwas stirred at 25° C. for 18 hrs. The reaction mixture was poured intoan aqueous solution (10 mL) of K₂HPO₄ (2 g). The solution was extractedwith EtOAc (3×15 mL). The combined EtOAc extracts were dried over sodiumsulfate and concentrated to give the crude intermediate.

Pd—C (5 mg, 10 wt %) was added to a MeOH solution (2 mL) of the crudeintermediate. HCl in MeOH (0.5 mL, 0.5 N) was added and the reaction wasstirred under H₂ (balloon) at 25° C. for 2 hrs. The catalyst wasfiltered off with a pad of Celite. The filtrate was concentrated toafford the crude product, which was purified by HPLC on a Polymerx 10μRP-γ□ 100 R column [30×21.20 mm, 10 micron, solvent A: 0.05 N HCl,solvent B: CH₃CN, sample in 2.0 mL (0.05 N HCl), gradient elution with0→70% B over 15 min, mass-directed fraction collection], yielding 2 mgof the desired product S3-5-1 as a yellow solid (54%, two steps): ¹H NMR(400 MHz, CD₃OD) δ 6.94 (d, J=6.0 Hz, 1H), 4.33 (s, 2H), 4.12 (s, 1H),3.03 (s, 3H), 2.96 (s, 3H), 3.18-2.95 (m, 3H), 2.27 (t, J=16.4 Hz, 1H),2.24-2.17 (m, 1H), 1.67-1.57 (m, 1H); MS (ESI) m/z 463.37 (M+H).

Methanesulfonic anhydride (99 mg, 0.57 mmol, 3.0 equiv) was added to asolution of S3-2 (0.16 g, 0.19 mmol, 1.0 equiv) in THF (4 mL). After 1h, triethylamine (0.079 mL, 0.57 mmol, 3.0 equiv) was added. After 1 h,additional methanesulfonic anhydride (0.16 g, 095 mmol, 5.0 equiv) wasadded. After 1 h, the reaction mixture was used without concentration insubsequent reactions: MS (ESI) m/z 911.45, 913.44 (M+H).

3,3-Dimethylbutylamine (0.063 mL, 0.47 mmol, 10 equiv) was added to asolution of S3-3 in THF (1 mL, 0.047 mmol, 1.0 equiv). After 1 h,additional 3,3-dimethylbutylamine (0.13 mL, 0.95 mmol, 20 equiv) wasadded. After 30 minutes, the reaction mixture was concentrated underreduced pressure. The crude product was purified by preparative reversephase HPLC on a Waters Autopurification system using a Sunfire Prep C18OBD column [5 μm, 19×50 mm; flow rate, 20 mL/min; Solvent A: H₂O with0.1% HCO₂H; Solvent B: CH₃CN with 0.1% HCO₂H; gradient: 20→100% B over15 min; mass-directed fraction collection]. Fractions containing thedesired product, eluting at 8.2-9.0 min, were collected and freeze-driedto yield 10 mg (22%) of compound S3-4-2: ¹H NMR (400 MHz, CDCl₃) δ16.10-15.79 (br s, 1H), 7.60-7.45 (m, 4H), 7.43-7.28 (m, 6H), 5.35 (s,2H), 5.04-4.84 (m, 2H), 3.90 (d, J=11.0 Hz, 1H), 3.32-3.19 (m, 1H),3.06-2.93 (m, 1H), 2.86-2.76 (m, 1H), 2.60-2.34 (m, 10H), 2.18-2.10 (m,1H), 1.70-1.58 (m, 4H), 0.99-0.76 (m, 18H), 0.26 (s, 3H), 0.11 (s, 3H);MS (ESI) m/z 916.54, 918.49 (M+H).

A solution of compound S3-4-2 (10 mg, 0.011 mmol) in 1,4-dioxane (0.80mL) was treated with HF (0.40 mL, 48-50% aqueous solution). Afterstirring overnight, the mixture was poured into a solution of K₂HPO₄(4.8 g) in water (20 mL). This mixture was extracted with EtOAc (3times). The combined extracts were dried over sodium sulfate, filtered,and concentrated under reduced pressure to yield the crude intermediate.

The above crude intermediate was dissolved in MeOH (1 mL), 1,4-dioxane(1 mL), and 0.5 N HCl/MeOH (0.4 mL). 10% Pd—C (Degussa, 2 mg) was added,and an atmosphere of hydrogen was introduced. After 2 hrs, the reactionmixture was filtered through Celite and concentrated under reducedpressure. The crude product was purified by preparative reverse phaseHPLC on a Waters Autopurification system using a Polymerx 10μ RP-γ□100 Rcolumn [30×21.20 mm, 10 micron, solvent A: 0.05 N HCl, solvent B: CH₃CN,gradient elution with 0→70% B over 10 min; mass-directed fractioncollection]. Fractions containing the desired product, eluting at8.2-9.6 min, were collected and freeze-dried to yield 5 mg (69%) ofcompound S3-5-2: ¹H NMR (400 MHz, CD₃OD/DCl) δ 7.08 (d, J=5.48 Hz, 1H),4.29 (s, 2H), 4.16 (s, 1H), 3.34-2.96 (m, 11H), 2.36-2.25 (m, 2H),1.71-1.58 (m, 3H), 0.97 (s, 9H); MS (ESI) m/z 546.32 (M+H).

The following compounds were prepared according to the methods ofS3-5-2, substituting the appropriate amine for 3,3-dimethylbutylamine:

S3-5-3:

¹H NMR (400 MHz, CD₃OD/DCl) δ 7.07 (d, J=5.96 Hz, 1H), 4.32 (s, 2H),4.17 (s, 1H), 3.80-3.65 (m, 3H), 3.36-2.96 (m, 11H), 2.38-2.25 (m, 2H),1.62 (dd, J=14.0, 11.4 Hz, 1H), 1.18 (d, J=6.4 Hz, 6H); MS (ESI) m/z548.30 (M+H).

S3-5-4:

¹H NMR (400 MHz, CD₃OD/DCl) δ 6.55 (d, J=5.60 Hz, 0.45H), 6.45 (d,J=5.52 Hz, 0.55H), 4.78 (s, 1.1H), 4.67 (s, 0.9H), 4.15 (s, 1H),3.40-2.96 (m, 16H), 2.32-2.20 (m, 4H), 2.10 (s, 2H), 1.62 (m, 1H), 1.02(s, 4H); MS (ESI) m/z 559.33 (M+H).

S3-5-5:

¹H NMR (400 MHz, CD₃OD) δ 7.06 (d, J=6.0 Hz, 1H), 4.46 (s, 2H), 4.09 (s,1H), 3.04 (s, 3H), 2.97 (s, 3H), 3.27-2.97 (m, 3H), 2.37 (m, 1H),2.28-2.14 (m, 3H), 2.08-2.00 (m, 2H), 1.72-1.62 (m, 1H); MS (ESI) m/z516.40 (M+H).

S3-5-6:

¹H NMR (400 MHz, CD₃OD/DCl) δ 7.22 (d, J=5.96 Hz, 1H), 4.39 (s, 2H),4.17 (s, 1H), 3.40 (s, 2H), 3.26-2.90 (m, 17H), 2.40-2.25 (m, 2H),1.70-1.57 (m, 1H), 1.32 (s, 6H); MS (ESI) m/z 575.37 (M+H).

Example 4 Synthesis of Compounds Via Scheme 4

The following compounds were prepared according to Scheme 4.

Compound S1-7 (0.50 g, 1.14 mmol, 1.0 equiv) and t-butylamine (0.60 mL,5.68 mmol, 5.0 equiv) were stirred at rt in toluene (5 mL) overnight.The reaction mixture was concentrated under reduced pressure. ¹H NMRindicated a 4:1 mixture of S4-1:S1-7. The material was redissolved intoluene (5 mL). t-Butylamine (0.60 mL, 5.68 mmol, 5.0 equiv) and 4 Åmolecular sieves (0.50 g) were added. After stirring at rt overnight,the reaction mixture was filtered through Celite and concentrated togive crude S4-1 (with ˜10% S1-7): ¹H NMR (400 MHz, CDCl₃) δ 8.32 (s,1H), 7.38 (d, J=6.0 Hz, 2H), 7.45-7.32 (m, 5H), 7.31-7.14 (m, 3H), 5.11(s, 2H), 2.35 (s, 3H), 1.38 (s, 9H).

A solution of S4-1 (0.56 g, 1.13 mmol, 1.2 equiv) in THE (5 mL) wasadded to a solution of LM DS (1.4 mL, 1.0 M/THF, 1.40 mmol, 1.5 equiv)and TMEDA (1.02 mL, 6.78 mmol, 6.0 equiv) in THF (10 mL) at −78° C. Nocolor change was observed. Additional LDA (1.22 mL, 1.2 M/THF, 1.47mmol, 1.3 equiv) was added dropwise, immediately producing a red coloredsolution. The reaction was stirred at −78° C. for 5 min. A solution ofenone S1-9 (0.45 g, 0.94 mmol, 1.0 equiv) in THF (3 mL) was addeddropwise to the reaction mixture. The reaction was stirred from −78° C.to −20° C. for 1 h, quenched by saturated aqueous NH₄Cl, and extractedwith EtOAc. The combined EtOAc extracts were dried (sodium sulfate) andconcentrated to yield the crude product, which was purified bypreparative reverse phase HPLC on a Waters Autopurification system usinga Sunfire Prep C18 OBD column [5 μm, 19×50 mm; flow rate, 20 mL/min;Solvent A: H₂O with 0.1% HCO₂H; Solvent 3: CH₃CN with 0.1% HCO₂H;gradient: 90→100% B over 15 min; mass-directed fraction collection].Fractions containing the desired product, eluting at 5.8-7.4 min, werecollected and concentrated under reduced pressure to give 0.23 g (29%)of pure S4-2 (The imine hydrolyzed to the aldehyde on concentration): ¹HNMR (400 MHz, CDCl₃) δ 15.79 (s, 1H), 10.33 (s, 1H), 7.60-7.45 (m, 4H),7.45-7.30 (m, 6H), 5.28 (s, 2H), 4.98 (q, J=9.2 Hz, 2H), 3.89 (d, J=10.4Hz, 1H), 3.30-3.22 (m, 1H), 3.08-2.95 (m, 1H), 2.62-2.57 (m, 1H),2.52-2.32 (m, 8H), 2.20-2.12 (m, 1H), 0.81 (s, 9H), 0.26 (s, 3H), 0.12(s, 3H); MS (ESI) m/z 831.56, 833.55 (M+H).

Cyclopropylamine (0.030 mL, 0.42 mmol, 7.0 equiv) was added to asolution of S4-2 (50 mg, 0.060 mmol, 1.0 equiv) and acetic acid (0.024mL, 0.42 mmol, 7.0 equiv) in dichloromethane (1 mL). After 30 min.,sodium triacetoxyborohydride (64 mg, 0.30 mmol, 5.0 equiv) was added.After an additional 3 hrs, the mixture was quenched by NaHCO₃(saturated, aqueous solution) and pH 7 phosphate buffer. The mixture wasextracted with dichloromethane, and the combined extracts were driedover sodium sulfate, filtered, and concentrated under reduced pressure.The crude product was purified by preparative reverse phase HPLC on aWaters Autopurification system using a Sunfire Prep C18 OBD column [5μm, 19×50 mm; flow rate, 20 mL/min; Solvent A: H₂O with 0.1% HCO₂H;Solvent B: CH₃CN with 0.1% HCO₂H; gradient: 20→100% B over 15 min;mass-directed fraction collection]. Fractions containing the desiredproduct, eluting at 8.6-10.4 min, were collected and freeze-dried toyield 8 mg of compound S4-3-1 (16%, ˜90% pure by ¹H NMR): ¹H NMR (400MHz, CDCl₃) δ 16.00-15.79 (br s, 1H), 7.60-7.45 (m, 4H), 7.43-7.26 (m,6H), 4.97 (q, J=9.4 Hz, 2H), 4.37 (br s, 2H), 3.90 (d, J=10.4 Hz, 1H),3.30-3.22 (m, 1H), 3.08-2.95 (m, 1H), 2.62-2.27 (m, 12H), 2.18-2.10 (m,1H), 0.88-0.74 (m, 11H), 0.70-0.62 (m, 2H), 0.26 (s, 3H), 0.12 (s, 3H);MS (ESI) m/z 872.43, 874.41 (M+H).

A solution of compound S4-3-1 (8 mg, 0.0094 mmol) in 1,4-dioxane (1 mL)was treated with HF (0.40 mL, 48-50% aqueous solution). After stirringat rt overnight, the mixture was poured into a solution of K₂HPO₄ (4.8g) in water (20 mL). This mixture was extracted with EtOAc (3 times),and the combined extracts were dried over sodium sulfate, filtered, andconcentrated under reduced pressure to yield the crude product.

The above crude product was dissolved in MeOH (1 mL), 1,4-dioxane (1mL), and 0.5 N HCl/MeOH (0.5 mL). 10% Pd—C (Degussa, 2 mg) was added,and an atmosphere of hydrogen was introduced. After 2 hrs, the reactionmixture was filtered through (Celite and concentrated under reducedpressure. The crude product was purified by preparative reverse phaseHPLC on a Waters Autopurification system using a Polymerx 10μ RP-γ100 R.column [30×21.20 mm, 10 micron, solvent A: 0.05 N HCl, solvent B: CH₃CN,gradient elution with 0→70% B over 10 min; mass-directed fractioncollection]. Fractions containing the desired product, eluting at6.8-7.6 min, were collected and freeze-dried to yield 3 mg (56%) ofcompound S4-5-1: ¹H NMR (400 MHz, CD₃OD/DCl) δ 7.08 (d, J=5.96 Hz, 1H),4.38 (s, 2H), 4.18 (s, 1H), 3.34-2.96 (m, 9H), 2.86-2.79 (m, 1H),2.36-2.25 (m, 2H), 1.62 (dd, J=14.0, 11.0 Hz, 1H), 1.02-0.86 (m, 4H); MS(ESI) m/z 502.22 (M+H).

The following compounds were prepared according to the methods ofS4-5-1, substituting the appropriate amines for cyclopropylamine.

S4-5-2:

¹H NMR (400 MHz, CD₃OD/DCl) δ 7.11 (d, J=5.48 Hz, 1H), 4.51 (dd, J=13.3,6.4 Hz, 1H), 4.31 (dd, J=13.3, 6.4 Hz, 1H), 4.16 (s, 1H), 3.42-3.10 (m,4H), 3.10-2.97 (m, 7H), 2.85 (s, 3H), 2.39-2.25 (m, 2H), 1.62 (dd,J=14.0, 11.0 Hz, 1H), 1.41 (t, J=7.3 Hz, 3H); MS (ESI) m 504.22 (M+H).

S4-5-3:

¹H NMR (400 Mt-Hz, CD₃OD/DCl) δ 7.10 (d, J=5.96 Hz, 1H), 4.23 (s, 2H),4.17 (s, 1H), 3.35-2.96 (m, 13H), 2.40-2.25 (m, 2H), 1.63 (dd, J=14.0,11.0 Hz, 1H), 1.39 (t, J=7.1 Hz, 6H); MS (ESI) m/z 518.24 (M+H).

S4-5-4:

¹H NMR (400 MHz, CD₃OD/DCl) δ 7.22 (d, J=5.48 Hz, 1H), 4.60 (s, 2H),4.16 (s, 1H), 3.98-3.60 (br m, 8H), 3.24-2.94 (m, 12H), 2.40-2.24 (m,2H), 1.64 (dd, J=14.0, 11.0 Hz, 1H); MS (ESI) m/z 545.26 (M+H).

Prepared according to the method of compound S4-3-1 above, substituting2-methoxyethylamine for cyclopropylamine: ¹H NMR (400 MHz, CDCl₃) δ16.00-15.79 (br s, 1H), 7.58-7.45 (m, 4H), 7.42-7.30 (m, 6H), 5.36 (s,2H), 5.02-4.88 (m, 2H), 4.35-4.20 (m, 2H), 3.95-3.88 (m, 1H), 3.75-58(m, 2H), 3.35 (s, 3H), 3.30-3.19 (m, 1H), 3.08-2.95 (br m, 3H),2.62-2.36 (m, 9H), 2.18-2.10 (m, 1H), 0.81 (s, 9H), 0.26 (s, 3H), 0.12(s, 3H); MS (ESI) m/z 890.55, 892.53 (M+H).

Formaldehyde (37% aqueous solution, 0.0092 mL, 0.12 mmol, 5.0 equiv) wasadded to a solution of compound S4-3-2 (22 mg, 0.025 mmol) indichloromethane (1 mL) and HOAc (0.0071 mL, 0.12 mmol, 5.0 equiv). After30 minutes, Na(OAc)₃BH (16 mg, 0.074 mmol, 3.0 equiv) was added. After 2hrs, the mixture was quenched by NaHCO₃ (saturated, aqueous solution)and pH 7 phosphate buffer. This mixture was extracted withdichloromethane, and the combined extracts were dried over sodiumsulfate, filtered, and concentrated under reduced pressure.

The above crude intermediate was dissolved in 1,4-dioxane (0.80 mL) andtreated with HF (0.40 mL, 48-500% aqueous solution) at rt. Afterstirring overnight, the mixture was poured into a solution of K₂HPO₄(4.8 g) in water (20 mL) and extracted with EtOAc (3 times). Thecombined extracts were dried over sodium sulfate, filtered, andconcentrated under reduced pressure.

The above crude intermediate was dissolved in MeOH (1 mL), 1,4-dioxane(1 mL), and 0.5 N HCl/MeOH (0.5 mL). 10% Pd—C (Degussa, 2 mg) was added,and an atmosphere of hydrogen was introduced. After 2 hrs, the reactionmixture was filtered through Celite and concentrated under reducedpressure to afford the crude product, which was purified by preparativereverse phase HPLC on a Waters Autopurification system using a Polymerx10μ RP-γ 100 R column [30×21.20 mm, 10 micron, solvent A: 0.05 N HCl,solvent B: CH₃CN, gradient elution with 0→70% B over 10 min;mass-directed fraction collection]. Fractions containing the desiredproduct, eluting at 6.5-7.6 min, were collected and freeze-dried toyield 11 mg of compound S4-5-5 (75%, 3 steps): ¹H NMR (400 MHz,CD₃OD/DCl) δ 7.10 (d, J=5.52 Hz, 1H), 4.59 (dd, J=13.3, 7.8 Hz, 1H),4.34 (dd, J=13.3, 7.8 Hz, 1H), 4.17 (s, 1H), 3.84-3.72 (m, 2H),3.54-3.35 (m, 5H), 3.34-2.96 (m, 9H), 2.91 (s, 3H), 2.38-2.25 (m, 2H),1.70-1.55 (m, 1H); MS (ESI) m/z 534.25 (M+H).

Prepared according to the methods of S4-5-5, substitutingcyclopropanemethylamine for 2-methoxyethylamine: ¹H NMR (400 MHz,CD₃OD/DCl) δ 7.12 (d, J=5.52 Hz, 1H), 4.62 (dd, J=13.3, 7.8 Hz, 1H),4.32 (dd, J=13.3, 7.8 Hz, 1H), 4.16 (s, 1H), 3.35-2.96 (m, 11H), 2.90(s, 3H), 2.40-2.26 (m, 2H), 1.63 (dd, J=14.0, 11.4 Hz, 1H), 1.30-1.17(m, 1H), 0.86-0.74 (m, 2H), 0.56-0.43 (m, 2H); MS (ESI) m/z 530.25(M+H).

Example 5 Synthesis of Compounds Via Scheme 5

The following compounds were prepared according to Scheme 5.

Methylmagnesium bromide (0.51 mL, 3.0 M/Et₂O, 1.53 mmol, 1.0 equiv) wasadded to a solution of compound S1-7 (0.67 g, 1.52 mmol, 1.0 equiv) inTHF (8 mL) at −78° C. After 30 minutes, the reaction mixture wasquenched by NH₄Cl (saturated, aqueous solution) and extracted withEtOAc. The extracts were washed with brine, dried over sodium sulfate,filtered, and concentrated under reduced pressure. The material waspurified by column chromatography on silica (Biotage 10 g prepackedcolumn, 0% to 25° % EtOAc in hexanes gradient), yielding 0.50 g (72%) ofcompound S5-1: R_(f) 0.35 (30% EtOAc/hexanes); ¹H NMR (400 MHz, CDCl₃) δ7.52-7.46 (m, 2H), 7.40-7.32 (m, 5H), 7.28-7.20 (m, 1H), 7.08-7.00 (m,2H), 5.41 (q, J=6.9 Hz, 1H), 5.09 (s, 2H), 2.34 (s, 1H), 1.63 (d, J=6.9Hz, 3H); MS (ESI) m/z 481.14, 483.1 (M+Na).

Manganese dioxide (activated, 0.20 g, 2.07 mmol, 5.0 equiv) was added toa solution of compound S5-1 (0.19 g, 0.41 mmol, 1.0 equiv) indichloromethane (5 m L). After stirring overnight, the reaction was ˜30%complete. Additional manganese dioxide (activated, 0.20 g, 2.07 mmol,5.0 equiv) was added. After stirring overnight, the reaction mixture wasdiluted with EtOAc (20 mL) and filtered through Celite. The filtrate wasconcentrated under reduced pressure, yielding 0.16 g (83%) of compoundS5-2: R_(f) 0.24 (10% EtOAc/hexanes); MS (ESI) m/z 479.10, 481.10(M+Na).

Compound S5-2 (55 mg, 0.12 mmol, 1.0 equiv), piperidine (0.059 mL, 0.60mmol, 5.0 equiv), and titanium(IV) isopropoxide (0.18 mL, 0.60 mmol, 5.0equiv) were stirred in dichloromethane (0.20 mL) overnight. Additionalpiperidine (0.20 mL, 2.00 mmol, 1.7 equiv) and titanium(IV) isopropoxide(0.20 mL, 0.67 mmol, 5.6 equiv) were added, and the reaction mixture washeated to 50° C. overnight. The reaction mixture was diluted with MeOH(2 mL) and NaBH₄ (15 mg, 0.40 mmol, 3.3 equiv) was added. AdditionalNaBH₄ (10 mg portions, 0.26 mmol, 2.2 equiv) was added every 30 minutesfor 4 hrs, resulting in 75 conversion. More MeOH (10 mL) and NaBH₄ (0.10g, 2.64 mmol, 22 equiv) were added. After bubbling ceased, the reactionmixture was concentrated under reduced pressure. The resulting solidswere dissolved in EtOAc, washed with NaHCO₃ (saturated, aqueoussolution, 3 times) and brine, dried over sodium sulfate, filtered, andconcentrated under reduced pressure, yielding 55 mg (87% crude) ofcompound S5-3-1. The material was concentrated from toluene (2 times)and used without further purification: R_(f) 0.35 (30% EtOAc/hexanes; MS(ESI) m/z 526.18, 528.17 (M+H).

n-Butyllithium (0.074 mL, 2.5 M/hexanes, 0.18 mmol, 2.25 equiv) wasadded to diisopropylamine (0.026 mL, 0.18 mmol, 2.25 equiv) in THF (2mL) at −40° C. The reaction mixture was cooled to −78° C., and TMEDA(0.072 mL, 0.48 mmol, 6.0 equiv) was added. A solution of compoundS5-3-1 (55 mg, 0.10 mmol, 1.25 equiv) in THF (1 mL) was added dropwise.The reaction was stirred at −78° C. for 5 min. A solution of enone S1-9(39 mg, 0.080 mmol, 1.0 equiv) in THF (0.5 mL) was added dropwise to thereaction mixture. Additional LDA (20.050 mL, 2.0M/heptane/THF/ethylbenzene, 0.10 mmol, 1.25 equiv) was added. Thereaction was stirred from −78° C. to −20° C. for 45 minutes, quenched bysaturated aqueous NH₄Cl, and extracted with EtOAc (2 times). Thecombined EtOAc extracts were dried (sodium sulfate) and concentrated toyield the crude product, which was purified by preparative reverse phaseHPLC on a Waters Autopurification system using a Sunfire Prep C18 OBDcolumn [5 μm, 19×50 mm; flow rate, 20 mL/min; Solvent A: H₂O with 0.1%HCO₂H; Solvent B: CH₃CN with 0.1% HCO₂H; gradient: 20→100% B over 15min; mass-directed fraction collection]. Fractions containing thedesired product, eluting at 7.2-8.6 min, were collected and freeze-driedto give 26 mg of compound S5-4-1 (36%): ¹H NMR (400 MHz, CDCl₃) δ16.0-15.9 (m, 1H), 7.58-7.45 (m, 4H), 7.40-7.28 (m, 6H), 5.35 (s, 2H),5.03-4.89 (m, 2H), 4.52-4.34 (br s, 1H), 3.92 (d, J=10.4 Hz, 1H),3.29-3.19 (m, 1H), 3.06-2.93 (m, 1H), 2.78-2.58 (m, 1H), 2.58-2.34 (m,11H), 2.22-1.76 (br m, 2H), 1.72-1.36 (br m, 9H), 0.88-0.76 (m, 9H),0.26 (s, 3H), 0.12 (s, 3H); MS (ESI) m/z 914.30, 916.32 (M+H).

A solution of compound S5-4-1 (26 mg, 0.028 mmol) in 1,4-dioxane (1 mL)was treated with HF (0.40 mL, 48-50% aqueous solution). After stirringovernight, the mixture was poured into a solution of K₂HPO₄ (4.8 g) inwater (20 mL). This mixture was extracted with EtOAc (3 times). Thecombined extracts were dried over sodium sulfate, filtered, andconcentrated under reduced pressure.

The above material was dissolved in MeOH (2 mL), 1,4-dioxane (2 mL), and0.5 N HCl/MeOH (0.5 mL). 10% Pd—C (Degussa, 5 mg) was added, and anatmosphere of hydrogen was introduced. After 2 hrs, the reaction mixturewas filtered through Celite and concentrated under reduced pressure. Thecrude product was purified by preparative reverse phase HPLC on a WatersAutopurification system using a Polymerx 10μ RP-γ100 R column [30×21.20mm, 10 micron, solvent A: 0.05 N HCl, solvent B: CH₃CN, gradient elutionwith 0→70% B over 10 min; mass-directed fraction collection]. Fractionscontaining the desired product, eluting at 6.8-8.2 min, were collectedand freeze-dried to yield 12 mg (68%) of compound S5-5-1: ¹H NMR (400MHz, CD₃OD/DC) δ 7.17 (d, J=5.0 Hz, 1H), 4.80-4.68 (m, 1H), 4.15 (s,1H), 3.80-3.72 (m, 1H), 3.42-3.30 (m, 1H), 3.26-2.78 (m, 11H), 2.40-2.25(m, 2H), 2.05-1.71 (m, 8H), 1.70-1.40 (m, 2H); MS (ESI) m/z 544.15(M+H).

Example 6 Synthesis of Compounds Via Scheme 6

The following compounds were prepared according to Scheme 6.

Compound S3-1 (0.36 g, 0.81 mmol, 1.0 equiv) was dissolved in1,2-dichloroethane (15 mL) with triethylamine (0.57 mL, 4.07 mmol, 5.0equiv). Methanesulfonic anhydride (0.71 g, 4.07 mmol, 5.0 equiv) wasadded in one portion at 0° C. During the addition, color change wasobserved. After stirring at rt for one hour, LC/MS indicated that thestarting material was consumed. The reaction mixture was diluted withdichloromethane, quenched by pH 7 phosphate buffer, washed with water(2×20 mL) and brine, dried over sodium sulfate, filtered, andconcentrated under reduced pressure. The crude intermediate was usedwithout further purification.

The above crude intermediate (0.16 g, 0.30 mmol, 1.0 equiv) wasdissolved in 1,2-dichloroethane (2 mL) with diisopropylethylamine (0.13mL, 0.72 mmol, 2.4 equiv). 2,2-Dimethyl piperidine hydrochloric salt (54mg, 0.36 mmol, 1.2 equiv) was first neutralized with sodium hydroxidesolution and then was added to reaction mixture in one portion at rt.After stirring at 60° C. for four days, LC/MS indicated that most of thestarting material was consumed. The reaction mixture was diluted withdichloromethane, washed with water (2×20 mL) and brine, dried oversodium sulfate, filtered, and concentrated under reduced pressure toafford the desired product S6-2-1, which was used without furtherpurification.

A solution of LDA was prepared by adding n-BuLi (0.31 mL, 1.6 M/hexanes,0.50 mmol, 2.5 equiv) to diisopropylamine (71 μL, 0.50 mmol, 2.5 equiv)in 2 mL dry THF under a nitrogen atmosphere in a flame dried schenckflask at −78° C. The pale solution was warmed to −20° C., stirred for 15min, and cooled down to −78° C. TMEDA (75 μL, 0.50 mmol, 2.5 equiv) wasadded slowly via a syringe, followed by the dropwise addition ofcompound S6-2-1 (crude, 0.30 mmol, 1.5 equiv)/THF (1 mL). A dark-redcolor appeared as soon as addition started. After stirring for 10 min,enone S1-9 (96 mg, 0.20 mmol, 1.0 equiv) in 1 mL dry THE was addedslowly via a syringe. After 10 min, LC/MS indicated that the enone wasconsumed and the product present. The reaction mixture was allowed toslowly warm to −20° C. in 1 h. Phosphate buffer (pH 7, 10 mL) andsaturated aqueous ammonium chloride (20 mL) were added. The resultingmixture was extracted with dichloromethane (3×15 mL), and the combinedextracts were dried over sodium sulfate, filtered, and concentratedunder reduced pressure to yield crude S6-3-1 as a red-orange oil (97mg).

Aqueous HF (0.3 mL, 48-50%) was added to a CH₃CN solution (1.0 mL) ofS6-3-1 (97 mg) in a plastic vial at 25° C. The reaction was stirred at25° C. for 18 hrs. The reaction mixture was poured into an aqueoussolution (10 mL) of K₂HPO₄ (2 g). The solution was extracted with EtOAc(3×15 mL). The combined EtOAc extracts were dried over sodium sulfateand concentrated to give the crude intermediate (18 mg).

Pd—C (5 mg, 10 wt %) was added to a MeOH solution (2 mL) of the abovecrude intermediate. HCl in MeOH (0.5 N, 0.5 mL) was added. The reactionwas stirred under H₂ (balloon) at 25° C. for 2 hrs and filtered througha pad of Celite. The filtrate was concentrated, and the crude productwas purified by HPLC on a Polymerx 10μ. RP-γ100 R column [30×21.20 mm,10 micron, solvent A: 0.05 N HCl, solvent B: CH₃CN, sample in 2.0 mL(0.05 N HCl), gradient elution with 0→70% B over 15 min, mass-directedfraction collection]. Fractions containing the desired product werecollected and freeze-dried, yielding 9 mg of the desired product S6-4-1as a yellow solid (5%, five steps): ¹H NMR (400 MHz, CD₃OD) δ 7.04 (d,J=5.5 Hz, 1H), 4.75 (dd, J=13.7, 7.3 Hz, 1H), 4.08 (s, 1H), 3.92 (dd,J=13.7, 7.3 Hz, 1H), 3.32 (m, 2H), 3.24-2.98 (m, 3H), 3.03 (s, 3H), 2.96(s, 3H), 2.37 (t, J=15.1 Hz, 1H), 2.27-2.20 (m, 1H), 1.91-1.82 (m, 2H),1.80-1.63 (m, 51H), 1.63 (s, 3H), 1.50 (s, 3H); MS (ESI) in m/z 558.30(M+H).

The following compounds were prepared similarly to S6-4-1.

¹H NMR (400 MHz, CD₃OD) δ 9.11 (s, 1H), 7.68 (m, 1H), 7.62 (m, 1H), 6.86(d, J=5.9 Hz, 1H), 5.54 (s, 2H), 4.07 (s, 1H), 3.22-2.93 (m, 9H),2.37-2.27 (m, 1H), 2.24-2.17 (m, 1H) 1.70-1.57 (m, 1H); MS (ESI) m/z513.17 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.06 (dd, J=8.2, 6.0 Hz, 1H), 4.39 (s, 2H),4.10 (s, 1H), 3.65-3.54 (m, 2H), 3.24-92 (m, 9H), 2.43-2.32 (m, 1H),2.28-2.17 (m, 1H), 2.07-1.58 (m, 7H), 1.51 (d, J=6.0 Hz, 3H), 1.39 (d,J=6.0 Hz, 3H); MS (ESI) m/z 558.61 (M+H).

Example 7 Synthesis of Compounds Via Scheme 7

The following compounds were prepared according to Scheme 7.

To a solution of sodium bicarbonate (0.21 g, 2.48 mmol, 1.1 equiv) inwater (10 mL) was added O-benzylhydroxylamine hydrochloride (0.40 g,2.48 mmol, 1.1 equiv). The solution was heated until all soliddissolved. Compound S1-7 (1.00 g, 2.26 mmol, 1.0 equiv) in EtOH (6 mL)and 1,4-dioxane (6 mL) were added. The solution was heated until allsolid dissolved, and then stirred at rt for 2 hrs. The mixture wasdiluted with EtOAc (100 mL), washed with brine (20 mL×3), dried (sodiumsulfate), and concentrated. The residue was purified by flashchromatography on silica gel, eluting with hexanes/EtOAc (30:1 to 5:1)to afford 1.10 g (89%) of compound S7-1: ¹H NMR (400 MHz, CDCl₃) δ 8.33(s, 1H), 7.48-7.24 (comp, 13H), 7.03-6.96 (comp, 2H), 5.22 (s, 2H), 5.03(s, 2H), 2.30 (d, J:=2.4 Hz, 3H); MS (ESI) m/z 548.16 (M+H).

To a solution of LDA (0.38 mL, 1.0 M/THF, 0.38 mmol, 2.9 equiv) in THF(1 mL) was added TMEDA (57 μL, 0.38 mmol, 2.9 equiv) at −78° C. Afterstirring for 5 min, a solution of compound S7-1 (89 mg, 0.16 mmol, 1.2equiv) in THF (0.3 mL) was added dropwise to the LDA solution. Aftercomplete addition, the reaction mixture was stirred at −78° C. for 10min. A solution of enone S1-9 (60 mg, 0.13 mmol, 1.0 equiv) in THF (0.3mL) was added dropwise. The mixture was slowly warmed to −20° C. over 30min. The mixture was quenched by phosphate buffer (pH 8, 1.5 mL) andsaturated ammonium chloride solution (0.5 mL). The aqueous layer wasextracted with EtOAc (3 mL×4). All organic layers were combined, dried(sodium sulfate), and concentrated. The crude product was purified bypreparative reverse phase HPLC on a Waters Autopurification system usinga Sunfire Prep C18 OBD column [5 μm, 19×50 mm; flow rate, 20 mL/min;Solvent A: H₂O with 0.1% HCO₂H; Solvent B: CH₃CN with 0.1% HCO₂H;injection volume: 2.0 mL. (CH₃CN); gradient: 80→100% B over 15 min;mass-directed fraction collection]. Fractions containing the desiredproduct, eluting at 6.1-8.3 min, were collected and freeze-dried to give33 mg of S7-2 (32%): ¹H NMR (400 MHz, CDCl₃) δ 15.71 (s, 1H), 7.55-7.24(comp, 10H), 5.35 (s, 2H), 4.99 (d, J=9.8 Hz, 1H), 4.95 (d, J=9.8 Hz,1H), 3.87 (d, J=10.4 Hz, 1H), 3.24 (dd, J=16.5, 4.6 Hz, 1H), 3.07-2.97(m, 1H), 2.49 (s, 6H), 2.64-2.33 (comp, 3H), 2.20-2.12 (m, 1H), 0.80 (s,9H), 0.26 (s, 3H), 0.12 (s, 3H); MS (ESI) m/z 828.16 (M+H).

To a solution of S7-2 (33 mg, 0.040 mmol) in acetonitrile (1 mL) wasadded HF (0.3 mL, 48-50% solution in water). The mixture was stirred at0° C. for 63 hrs and rt for 3 hrs. The mixture was quenched by potassiumphosphate dibasic solution (prepared from 8 g K₂HPO₄ and 8 mL water).The aqueous layer was extracted with EtOAc (8 mL×5). All organic layerswere combined, dried (sodium sulfate) and concentrated to afford thecrude intermediate.

To the above crude intermediate in MeOH/dioxane solution (1:1, 1.4 mL)was added Pd—C (15 mg, 10 wt %) and HCl/MeOH (0.5 N, 0.25 mL). Thereaction was bubbled with H₂ (balloon) at 25° C. for 90 min. The mixturewas filtered through a small Celite plug and flashed with MeOH. Thefiltrate was concentrated to yield the crude product, which was purifiedby preparative reverse phase HPLC on a Waters Autopurification systemusing a Phenomenex Polymerx 10μ RP-□ 100A column [10 μm, 150×21.20 mm;flow rate, 20 mL/min; Solvent A: 0.05 N HCl/water; Solvent B: CH₃CN;injection volume: 4.5 mL (0.05 N HCl/water); gradient: 0-50% B over 10min; mass-directed fraction collection]. Fractions containing thedesired product, eluting at 6.9-8.1 min, were collected and freeze-driedto yield 10 mg of primary S7-3 (55% for 2 steps): ¹H NMR (400 MHz,CD₃OD) δ 6.95 (d, J=6.1 Hz, 1H), 4.18 (s, 2H), 4.09 (s, 1H), 3.04 (s,3H), 2.96 (s, 3H), 3.22-2.90 (comp, 3H), 2.39-2.28 (m, 1H), 2.28-2.18(m, 1H), 1.70-1.57 (m, 1H); MS (ESI) m/z 462.12 (M+H).

To a solution of compound S7-3 (10 mg, 0.020 mmol, 1.0 equiv) and Ac₂O(diluted 20 times in dichloromethane, 45 μL, 0.020 mmol, 1.0 equiv) inDMF (1.5 mL) was added Et₃N (15 μL, 0.11 mmol, 5.5 equiv) at 0° C. Themixture was stirred for 30 min and then submitted to preparative reversephase HPLC purification on a Waters Autopurification system using aPhenomenex Polymerx 10μ RP-γ 100A column [10 μm, 150×21.20 mm; flowrate, 20 mL/min; Solvent A: 0.05 N HC/water; Solvent B: CH₃CN; injectionvolume: 3.0 mL (0.05 N HCl/water); gradient: 0→70% B over 20 min;mass-directed fraction collection]. Fractions containing the desiredproduct, eluting at 9.4-10.6 min, were collected and freeze-dried toyield 4 mg of S7-4-1 (40%):

¹H NMR (400 MHz, CD₃OD) δ 6.73 (d, J=5.5 Hz, 1H), 4.38 (d, J=1.8 Hz,2H), 4.07 (s, 1H), 3.15 (dd, J=15.3, 4.3 Hz, 1H), 3.03 (s, 3H), 2.95 (s,3H), 3.10-2.92 (comp, 2H), 2.32-2.23 (m, 1H), 2.22-2.15 (m, 1H), 2.01(s, 3H), 1.68-1.56 (m, 1H); MS (ESI) m/z 504.10 (M+H).

S7-4-2 was prepared according to the procedure for the preparation ofS7-4-1:

¹H NMR (400 MHz, CD₃OD) δ 6.65 (d, J=6.1 Hz, 1H), 4.41 (d, J=16.5 Hz,1H), 4.35 (d, J=16.5 Hz, 1H), 4.06 (s, 1H), 3.15 (dd, J=15.3, 4.6 Hz,1H), 3.03 (s, 3H), 2.95 (s, 3H), 3.10-2.91 (comp, 2H), 2.33-2.22 (m,1H), 2.22-2.14 (m, 1H), 1.68-1.56 (m, 1H), 1.22 (s, 9H); MS (ESI) m/z546.27 (M+H).

To a solution of compound S7-3 (11 mg, 0.020 mmol, 1.0 equiv) and methylisocyanate (1.4 mg, 0.020 mmol, 1.0 equiv) in DMF (1.5 mL) was addedEt₃N (18 μL, 0.13 mmol, 6.5 equiv) at 0° C. The mixture was stirred for10 min and then submitted to preparative reverse phase HPLC purificationon a Waters Autopurification system using a Phenomenex Polymerx 10μ RP-γ100A column [10 μm, 150×21.20 mm; flow rate, 20 mL/min; Solvent A: 0.05N HCl/water; Solvent B: CH₃CN; injection volume: 3.3 mL (0.05 NHCl/water); gradient: 0→70% B over 20 min; mass-directed fractioncollection]. Fractions containing the desired product, eluting at9.3-10.6 min, were collected and freeze-dried to yield 4 mg of S7-4-3(31%): ¹H NMR (400 MHz, CD₃OD) δ 6.74 (d, J=6.1 Hz, 1H), 4.37 (d, J=17.3Hz, 1H), 4.32 (d, J=17.3 Hz, 1H), 4.06 (s, 1H), 3.15 (dd, J=15.9, 4.6Hz, 1H), 3.03 (s, 3H), 2.95 (s, 3H), 3.10-2.92 (comp, 2H), 2.72 (s, 3H),2.32-2.22 (m, 1H), 2.22-2.15 (m, 1H), 1.67-1.56 (m, 1H); MS (ESI) m/z519.08 (M+H).

S7-4-4 was prepared from S7-3 according to the procedure for thepreparation of S7-4-1: ¹H NMR (400 MHz, CD₃OD) δ 6.79 (d, J=6.1 Hz, 1H),4.49 (d, J=5.5 Hz, 2H), 4.07 (s, 1H), 4.03 (s, 2H), 3.15 (dd, J=15.2,4.3 Hz, 1H), 3.03 (s, 3H), 2.95 (s, 3H), 2.94 (s, 6H), 3.10-2.92 (comp,2H), 2.33-2.23 (m, 1H), 2.22-2.17 (m, 1H), 1.68-1.56 (m, 1H); MS (ESI)m/z 547.11 (M+H).

To a solution of compound S7-3 (11 mg, 0.020 mmol, 1.0 equiv) andmethanesulfonic anhydride (5 mg, 0.030 mmol, 1.5 equiv) in DMF (1.5 mL)was added Et₃N (18 μL, 0.13 mmol, 6.5 equiv) at 0° C. The mixture wasstirred for 50 min and then submitted to preparative reverse phase HPLCpurification on a Waters Autopurification system using a PhenomenexPolymerx 10μ RP-γ 100A column [10 μm, 150×21.20 mm; flow rate, 20mL/min; Solvent A: 0.05 N HCl/water; Solvent B: CH₃CN; injection volume:3 mL (0.05 N HCl/water); gradient: 0→70% B over 20 min; mass-directedfraction collection]. Fractions containing the desired product, elutingat 10.3-11.6 min, were collected and freeze-dried to yield 3 mg ofS7-4-5 (22%): ¹H NMR (400 MHz, CD₃OD) δ 6.93 (d, J=6.1 Hz, 1H), 4.29 (s,2H), 4.06 (s, 1H), 3.16 (dd, J=15.9, 4.6 Hz, 1H), 3.03 (s, 3H), 2.94 (s,3H), 2.93 (s, 3H), 3.10-2.92 (comp, 2H), 2.34-2.23 (m, 1H), 2.23-2.16(m, 1H), 1.68-1.57 (m, 1H); MS (ESI) m/z 540.04 (M+H).

S7-4-6 was prepared according to the procedure for the preparation ofS7-4-5:

¹H NMR (400 MHz, CD₃OD)) δ 7.79 (d, J=7.4 Hz, 2H), 7.59-7.48 (comp, 3H),6.76 (d, J=6.1 Hz, 1H), 4.12 (s, 2H), 4.06 (s, 1H), 3.03 (s, 3H), 2.95(s, 3H), 3.15-2.91 (comp, 3H), 2.24-2.13 (comp, 2H), 1.67-1.54 (m, 1H);MS (ESI),/z 602.22 (M+H).

The following compounds were prepared from S2-4-17 using similar amide,urea, or sulfonamide formation conditions.

To a solution of S2-4-17 (8 mg, 0.020 mmol, 1.0 equiv) and Ac₂O)(diluted 20 times in dichloromethane, 38 μL, 0.020 mmol, 1.0 equiv) inDMF/acetonitrile (1:1, 2 mL) was added Et₃N (9 μL, 0.070 mmol, 3.5equiv) at rt. The mixture was stirred for 30 min and then submitted topreparative reverse phase HPLC purification on a Waters Autopurificationsystem using a Phenomenex Polymerx 10μ RP-γ 100A column [10 μm,150×21.20 mm; flow rate, 20 mL/min; Solvent A: 0.05 N HCl/water; SolventB: CH₃CN; injection volume: 1.5 mL (0.05 N HCl/water); gradient: 0→100%B over 10 min; mass-directed fraction collection]. Fractions containingthe desired product, eluting at 8.1-9.0 min, were collected andfreeze-dried to yield 5 mg of S7-4-7 (52%):

¹H NMR (400 MHz, CD₃OD) δ 6.62 (d, J=6.1 Hz, 1H), 4.67-4.60 (m, 2H),4.07 (s, 1H), 3.09 (s, 3H), 3.03 (s, 3H), 2.95 (s, 3H), 3.21-2.90 (comp,3H), 2.36-2.12 (comp, 5H), 1.68-1.58 (m, 1H); MS (ESI) m/z 518.12 (M+H).

S7-4-8: ¹H NMR (400 MHz, CD₃OD) δ 6.64-6.56 (m, 1H), 4.63 (br s, 2H),4.07 (s, 1H), 3.25 (s, 3H), 3.03 (s, 3H), 2.95 (s, 3H), 3.21-2.92 (comp,3H), 2.35-2.16 (comp, 2H), 2.07-1.99 (m, 1H), 1.70-1.57 (m, 1H),0.94-0.76 (comp, 4H); MS (ESI) m/z 544.25 (M+H).

S7-4-9: ¹H NMR (400 MHz, CD₃OD) δ 6.53 (d, J=6.1 Hz, 1H), 4.63 (d, J=4.3Hz, 2H), 4.06 (s, 1H), 3.17 (s, 3H), 3.03 (s, 3H), 2.95 (s, 3H),3.20-2.92 (comp, 3H), 2.37-2.16 (comp, 2H), 1.68-1.58 (m, 1H), 1.32 (s,9H); MS (ESI) m/z 560.30 (M+H).

To a solution of S2-4-17 (15 mg, 0.030 mmol, 1.0 equiv) and methylisocyanate (2 mg, 0.030 mmol, 1.0 equiv) in DMF (1.5 mL) was added Et₃N(22 μL, 0.16 mmol, 5.3 equiv) at 0° C. The mixture was stirred for 30min and then submitted to preparative reverse phase HPLC purification ona Waters Autopurification system using a Phenomenex Polymerx 10μ RP-γ100A column [10 μm, 150×21.20 mm; flow rate, 20 mL/min; Solvent A: 0.05N HCl/water; Solvent B: CH₃CN; injection volume: 2.6 mL (0.05 NHCl/water); gradient: 0→100% B over 20 min; mass-directed fractioncollection]. Fractions containing the desired product, eluting at8.4-10.2 min, were collected and freeze-dried to yield 14 mg of S7-4-10(83%): ¹H NMR (400 MHz, CD₃OD) δ6.59 (d, J=6.1 Hz, 1H), 4.55 (s, 2H),4.07 (s, 1H), 3.03 (s, 3H), 2.95 (s, 3H), 2.91 (s, 3H), 3.19-2.89 (comp,3H), 2.75 (s, 3H), 2.32-2.16 (comp, 2H), 1.68-1.57 (m, 1H); MS (ESI) m/z533.11 (M+H).

To a solution of S2-4-17 (15 mg, 0.030 mmol, 1.0 equiv) andmethanesulfonic anhydride (6 mg, 0.030 mmol, 1.0 equiv) in DMF (1.5 mL)was added Et₃N (22 μL, 0.16 mmol, 5.3 equiv) at 0° C. The mixture wasstirred at 0° C. for 30 min and rt for 20 min. The mixture was submittedto preparative reverse phase HPLC purification on a WatersAutopurification system using a Phenomenex Polymerx 10 i RP-γ 100Acolumn [10 μm, 150×21.20 mm; flow rate, 20 mL/min; Solvent A: 0.05 NHCl/water; Solvent B: CH₃CN; injection volume: 3 mL (0.05 N HCl/water);gradient: 0→100% B over 20 min; mass-directed fraction collection].Fractions containing the desired product, eluting at 9.8-11.6 min, werecollected and freeze-dried to yield 7 mg of S7-4-11 (38%): ¹H NMR (400MHz, CD₃OD) δ 6.90 (d, J=5.5 Hz, 1H), 4.38 (s, 2H), 4.07 (s, 1H), 3.03(s, 3H), 2.95 (s, 3H), 2.94 (s, 3H), 3.19-2.93 (comp, 3H), 2.83 (s, 3H),2.34-2.16 (comp, 2H), 1.69-1.58 ((m, 1H)); MS (ESI) m/z 554.06 (M+H).

S7-4-12 was prepared according to the procedure for the preparation ofS7-4-11: ¹H NMR (400 MHz, CD₃OD) δ 7.85 (dd, J=7.4, 1.8 Hz, 2H),7.72-7.60 (comp, 3H), 6.87 (d, J=6.1 Hz, 1H), 4.25 (d, J=1.8 Hz, 2H),4.06 (s, 1H), 3.03 (s, 3H), 2.95 (s, 3H), 3.15-2.92 (comp, 3H), 2.71 (s,3H), 2.32-2.16 (comp, 2H), 1.68-1.57 (m, 1H); MS (ESI) m/z 616.20 (M+H).

Example 8 Synthesis of Compounds Via Scheme 8

The following compounds were prepared according to Scheme 8.

(Methoxymethyl)triphenylphosphonium chloride (0.46 g, 1.35 mmol, 2.0equiv) was added to a suspension of potassium t-butoxide (0.15 g, 1.35mmol, 2.0 equiv) in THF (3 mL), resulting in a red colored mixture.After 15 minutes, a solution of compound S1-7 (0.30 g, 0.68 mmol, 1.0equiv) in THF (2 mL) was added, resulting in a yellowish orange mixture.After 1 h, the reaction mixture was quenched by water (15 mL) andextracted with EtOAc (2×20 mL). The combined extracts were dried oversodium sulfate, filtered, and concentrated under reduced pressure. Thematerial was purified by column chromatography on silica (Biotage 10 gprepacked column, 0% to 6% EtOAc in hexanes gradient). The tworegioisomeric compounds mostly co-eluted and were combined, yielding0.23 g (73%) of compound S8-1 (¹H NMR indicated a 2:1 mixture of cis andtrans isomers): R_(f) 0.40, 0.34 (10% EtOAc/hexanes); ¹H NMR (400 MHz,CDCl₃) δ 7.52-7.46 (m, 2H), 7.40-7.32 (m, 5.66H), 7.28-7.20 (m, 1H),7.04 (d, J=8.2 Hz, 2H), 6.31 (d, J=6.8 Hz, 0.34H), 5.93 (d, J=12.8 Hz,0.66H), 5.22 (d, J=6.8 Hz, 0.34H), 5.08 (s, 2H), 3.77 (s, 2H), 3.73 (s,1H), 2.36-2.31 (m, 3H); MS (ESI) m/z 493.26, 495.26 (M+Na).

A solution of S8-1 (0.35 g, 0.74 mmol) in 6 N HCl in water (2 mL) andTHF (6 mL) was heated to 70° C. After 4 hrs, the reaction mixture wascooled to room temperature and diluted with EtOAc (25 mL). The layerswere separated, and the EtOAc layer was dried over sodium sulfate,filtered, and concentrated under reduced pressure, yielding 0.32 g (95%)of crude aldehyde intermediate: MS (ESI) m/z 479.19, 481.15 (M+Na).

The aldehyde intermediate (0.10 g, 0.13 mmol, 1.0 equiv) was dissolvedin 1,2-dichloroethane (2 mL) and HOAc (0.054 mL, 0.94 mmol, 7.2 equiv)and t-butylamine (0.099 mL, 0.94 mmol, 7.2 equiv) were added. After 15minutes, Na(OAc)₃BH (0.14 g, 0.67 mmol, 5.2 equiv) was added. Afterstirring overnight, the reaction mixture was quenched by NaHCO₃(saturated, aqueous solution), diluted with dichloromethane (20 mL),washed with NaHCO₃ (saturated, aqueous solution, 10 mL), dried oversodium sulfate, filtered, and concentrated under reduced pressure. Thematerial was purified by column chromatography on silica (Biotage 5 gprepacked column, 0% to 60% EtOAc in hexanes gradient), yielding 20 mg(28%) of compound S8-2-1: ¹H NMR (400 MHz, CDCl₃) δ 7.52-7.46 (m, 2H),7.40-7.32 (m, 5H), 7.28-7.20 (m, 1H), 7.04 (d, J=8.2 Hz, 2H), 5.10 (s,2H), 3.25-2.98 (m, 2H), 2.90-2.70 (m, 2H), 2.35 (s, 3H), 1.17 (br s,9H); MS (ESI) m/z 514.31, 516.3 (M+H).

A solution of S8-2-1 (20 mg, 0.038 mmol, 1.2 equiv) in THF (1 mL) wasadded to a solution of LDA (1.2 M/THF/heptane/ethylbenzene, 0.058 mL,0.070 mmol, 2.2 equiv) and TMEDA (0.028 mL, 0.19 mmol, 6.0 equiv) in THF(2 mL) at −78° C., giving a red colored solution. The reaction wasstirred at −78° C. for 5 min. A solution of enone S1-9 (15 mg, 0.032mmol, 1.0 equiv) in THF (0.5 mL) was added dropwise to the reactionmixture. The reaction was stirred from −78° C. to −20° C. for 1 h,quenched by saturated aqueous NH₄Cl, and extracted with EtOAc (2 times).The combined EtOAc extracts were dried (sodium sulfate) and concentratedto yield the crude product. The crude product was purified bypreparative reverse phase HPLC on a Waters Autopurification system usinga Sunfire Prep C18 OBD column [5 μm, 19×50 mm; flow rate, 20 mL/min;Solvent A: H₂O with 0.1% HCO₂H; Solvent B: CH₃CN with 0.1% HCO₂H;gradient: 20→100% B over 15 min; mass-directed fraction collection].Fractions containing the desired product, eluting at 7.0-8.0 min, werecollected and freeze-dried to give 18 mg of pure compound S8-3-1 (62%):¹H NMR (400 MHz, CDCl₃) δ 7.58-7.45 (m, 4H), 7.40-7.28 (m, 6H), 5.35 (s,2H), 5.00-4.87 (m, 2H), 3.91 (d, J=10.4 Hz, 1H), 3.54-3.15 (m, 3H),3.02-2.88 (m, 3H), 2.58-2.32 (m, 9H), 2.17-2.08 (m, 1H), 1.48-1.20 (brs, 9H), 0.80 (s, 9H), 0.26 (s, 3H), 0.11 (s, 3H); MS (ESI) m/z 902.48,904.45 (M+H).

A solution of compound S8-3-1 (18 mg, 0.020 mmol) in 1,4-dioxane (0.80mL) was treated with HF (0.40 mL, 48-50% aqueous solution). Afterstirring overnight, the mixture was poured into a solution of K₂HPO₄(4.8 g) in water (20 mL). This mixture was extracted with EtOAc (3times), and the combined extracts were dried over sodium sulfate,filtered, and concentrated under reduced pressure.

The above material was dissolved in MeOH (1 mL), 1,4-dioxane (1 mL), and0.5 N HCl/MeOH (0.4 mL). 10% Pd—C (Degussa, 2 mg) was added, and anatmosphere of hydrogen was introduced. After 2 hrs, the reaction mixturewas filtered through Celite and concentrated under reduced pressure. Thecrude product was purified by preparative reverse phase HPLC on a WatersAutopurification system using a Polymerx 10μ RP-γ 100 R column [30×21.20mm, 10 micron, solvent A: 0.05 N HCl, solvent B: CH₃CN, gradient elutionwith 0→70% B over 10 min; mass-directed fraction collection]. Fractionscontaining the desired product, eluting at 7.0-8.4 min, were collectedand freeze-dried to yield 8 mg of compound S8-4-1 (64%): ¹H NMR (400MHz, CD OD/DCl) δ 6.86 (d, J=5.5 Hz, 1H), 4.14 (s, 1H), 3.34-2.94 (m,13H), 2.33-2.21 (m, 2H), 1.70-1.55 (m, 1H), 1.49 (s, 9H); MS (ESI) m/z532.31 (M+H).

Example 9 Synthesis of Compounds Via Scheme 9

The following compounds were prepared according to Scheme 9.

Compound S1-7 (0.25 g, 0.56 mmol, 1.0 equiv) was dissolved in1,2-dichloroethane (4 mL). Dimethylamine (0.56 mL, 2.0 M/THF, 1.12 mmol,2.0 equiv) and acetic acid (64 μL, 1.12 mmol, 2.0 equiv) were addedunder a nitrogen atmosphere. After stirring at rt for 1 h, sodiumtriacetoxyborohydride (0.36 g, 1.68 mmol, 3.0 equiv) was added toreaction mixture. After overnight, LC/MS indicated that the startingmaterial was consumed. The reaction mixture was diluted withdichloromethane, washed with NaHCO₃ (saturated aqueous solution, 3×10mL) and brine, dried over sodium sulfate, filtered, and concentratedunder reduced pressure. The crude product was purified by flash columnchromatography (Biotage 10 g column, 10% to 30% EtOAc in hexanesgradient), yielding 0.21 g (78%) of the pure compound S9-1-1 as acolorless oil: ¹H NMR (400 MHz, CDCl₃) δ 7.52-7.47 (m, 2H), 7.40-7.33(m, 5H), 7.26 (t, J=7.8 Hz, 1H), 7.07-7.03 (m, 2H), 5.11 (s, 2H), 3.66(d, J=2.3 Hz, 2H), 2.37 (d, J=2.3 Hz, 3H), 2.35 (s, 6H).

Compound S9-1-1 (0.10 g, 0.21 mmol), methylboronic acid (38 mg, 0.64mmol), dichlorobis(tricyclohbexylphosphine)palladium(II) (4 mg, 0.011mmol) and K₃PO₄ (0.14 g, 0.64 mmol) were heated to 80° C. in toluene (2mL) and water (5 drops). After 5 hrs, additional K₃PO₄ (0.14 g, 0.64mmol) and methylboronic acid (38 mg, 0.64 mmol) were added. The reactionmixture was heated to 100° C. After one hour, the reaction mixture wascooled to rt and let stand for 3 days. Additionaldichlorobis-(tricyclohexylphosphine)palladium(II) (5 mg, 0.015 mmol) andmethylboronic acid (38 mg, 0.64 mmol) were added, followed by enoughK₃PO₄ to give a saturated aqueous layer. This was heated to 110° C.After 2 hrs, the reaction was complete. Upon cooling to rt, the reactionmixture was diluted with EtOAc, washed with water (2 times) and brine (1time), dried over sodium sulfate, filtered, and concentrated underreduced pressure. The material was purified by column chromatography onsilica (Biotage 5 g prepacked column, 0% to 6% MeOH in dichloromethanegradient), yielding 81 mg (93%) of compound S9-2-1. The compound was˜80-90% pure and contaminated with phosphine ligand: R_(f) 0.49 (10%MeOH/dichloromethane); ¹H NMR (400 MHz, CDCl₃) δ 7.50-7.30 (m, 7H),7.30-7.20 (m, 1H), 7.12-7.04 (m, 2H), 4.96 (s, 2H), 2.80-2.20 (m, 9H),1.56 (s, 3H); MS (ESI) m/z 408.34 (M+H).

n-Butyllithium (2.5 M/hexanes, 0.14 mL, 0.35 mmol, 2.3 equiv) was addedto a −40° C. solution of diisopropylamine (0.050 mL, 0.35 mmol, 2.3equiv) in THF (5 mL). The reaction mixture was cooled to −78° C., andTMEDA (0.14 mL, 0.92 mmol, 6.1 equiv) was added. A solution of S9-2-1(81 mg, 0.20 mmol, 1.3 equiv) in THF (2 mL) was added dropwise. Asolution of enone S1-9 (74 mg, 0.15 mmol, 1.0 equiv) in THF (1 mL) wasadded dropwise to the reaction mixture. The reaction was stirred from−78° C. to −20° C. for 1 h, quenched by saturated aqueous NH₄Cl, andextracted with EtOAc (2 times). The combined EtOAc extracts were dried(sodium sulfate) and concentrated to yield the crude product. The crudeproduct was purified by preparative reverse phase HPLC on a WatersAutopurification system using a Sunfire Prep C18 OBD column [5 μm, 19×50mm; flow rate, 20 mL/min; Solvent A: H₂O with 0.1% HCO₂H; Solvent B:CH₃CN with 0.1% HCO₂H; gradient: 50→100% B over 15 min; mass-directedfraction collection]. Fractions containing the desired product, elutingat 2.5-3.6 min, were collected and freeze-dried to give 34 mg ofcompound S9-3-1 (28%, contaminated with the phosphine ligand): MS (ESI)m/z 796.53 (M+H).

A solution of compound S9-3-1 (34 mg, 0.043 mmol) in 1,4-dioxane (0.9mL) was treated with HF (0.40 mL, 48-50% aqueous solution). Afterstirring overnight, the mixture was poured into a solution of K₂HPO₄(4.8 g) in water (20 mL). This mixture was extracted with EtOAc (3times), and the combined extracts were dried over sodium sulfate,filtered, and concentrated under reduced pressure.

The above crude material was dissolved in MeOH (2 mL), 1,4-dioxane (2mL), and 0.5 N HCl/MeOH (0.5 mL). 10% Pd—C (Degussa, 10 mg) was added,and an atmosphere of hydrogen was introduced. Upon completion, thereaction mixture was filtered through Celite and concentrated underreduced pressure. The crude product was purified by preparative reversephase HPLC on a Waters Autopurification system using a Polymerx 10μ RP-γ100 R column [30×21.20 mm, 10 micron, solvent A: 0.05 N HCl, solvent B:CH₃CN, gradient elution with 0→70% B over 10 min; mass-directed fractioncollection]. Fractions containing the desired product, eluting at6.6-7.6 min, were collected and freeze-dried to yield 10 mg of compoundS9-4-1 (41%): ¹H NMR (400 MHz, CD₃OD/DCl) δ 4.52 (s, 2H), 4.15 (s, 1H),3.24-2.92 (m, 15H), 2.36 (s, 3H), 2.34-2.24 (m, 2H), 1.70-1.56 (m, 1H);MS (ESI) m/z 504 (M+H).

Example 10 Synthesis of Compounds Via Scheme 10

The following compounds were prepared according to Scheme 10.

To a 250 mL round bottom flask was added compound S1-4 (14.47 g, 56.30mmol, 1.0 equiv, crude), tetrabutylammonium bromide (0.90 g, 2.80 mmol,0.05 equiv), 1,2-dichloroethane (60 mL), and water (60 mL). The clearbi-layer was cooled in a 20° C. water bath. Nitric acid (7.2 mL, 70 wt%, 112.60 mmol, 2.0 equiv) was added. After the addition, the reactiontemperature slowly rose to 26° C. The reaction was stirred at roomtemperature overnight (19 hrs). TLC (heptane/EtOAc=9.5/0.5) showed thereaction was complete. The organic layer was separated, washed withwater (60 mL×2) and brine, and dried over anhydrous sodium sulfate. Thesolvent was removed to give compound S10-1 as a brown oil, whichsolidified on standing (17.71 g, quantitative). The crude product wasused directly for the next step.

To a 250 mL round bottom flask was added compound S10-1 (17.7 g, 56.30mmol 1.0 equiv), acetone (177 mL), anhydrous potassium carbonate (15.6g, 113.00 mmol, 2.0 equiv), and potassium iodide (0.47 g, 2.80 mmol,0.05 equiv). To the stirred suspension at room temperature was addedbenzyl bromide (7.03 mL, 59.10 mmol, 1.05 equiv). The suspension wasthen heated to 56° C. for 4 hrs. TLC (heptane/EtOAc=9/1) showed thereaction was complete. The solid was removed by filtration and washedwith acetone (30 mL). The filtrated was concentrated to give a paste.The paste was partitioned between methyl t-butyl ether (MTBE, 120 mL)and water (80 mL). The organic layer was washed with water (80 mL) andbrine, dried over anhydrous sodium sulfate, and concentrated to givecompound S10-2 as a brown oil (21.09 g, 98%). The crude product was useddirectly for the next step.

To a 1 L round bottom flask was added compound S10-2 (21.08 g, 5540mmol, 1.0 equiv) and THF (230 mL). The solution was cooled in a coldwater bath to 10° C. To another 500 mL round bottom flask containingwater (230 mL), sodium hydrosulfite (Na₂S₂O₄, 56.7 g, 276.80 mmol, 5.0equiv) was added slowly with stirring. The aqueous solution of sodiumhydrosulfite was added to the THF solution of compound S10-2. Thetemperature quickly rose from 10° C. to 20.4° C. after the addition. Theyellow suspension was stirred while the cold water bath slowly warmed upto room temperature overnight to give an orange cloudy solution. Thereaction temperature during this period was between 15° C. to 19° C. TLC(heptane/EtOAc=9/1) showed the reaction was complete. The orange cloudysolution was diluted with EtOAc (460 mL). The organic layer was washedwith water (150 mL×2) and brine, dried over anhydrous sodium sulfate,and concentrated under reduced pressure to give the crude product as abrown oil. The crude product was purified by flash silica gel columneluted with heptane/EtOAc 9/1 to yield the desired product S10-3 (15.83g, 80%, 3 steps).

Di-t-butyl dicarbonate (10.56 g, 48.40 mmol, 2.5 equiv) and DMAP (0.12g, 0.97 mmol, 0.05 equiv) were added to the solution of S10-3 (6.80 g,19.40 mmol, 1.0 equiv) in anhydrous DMF (39 mL). The resulting mixturewas stirred at rt for 20 hrs and diluted with EtOAc. The solution waswashed with H₂O (three times) and brine, dried over sodium sulfate,filtered and concentrated. Further purification of the residue by flashchromatography (silica gel, 95:5 hexanes/EtOAc) yielded compound S10-4as a white solid (8.70 g, 81%): ¹H NMR (400 MHz, CDCl₃) δ 1.39 (s, 18H),2.36 (d, J=1.8 Hz, 3H), 4.92 (s, 2H), 6.96-7.02 (m, 3H), 7.22-7.38 (m,8H); MS (ESI) m/z 574.3 (M+Na), calcd for C₃₁H₃₄FNO₃Na 574.2.

To compound S10-4 (4.80 g, 8.70 mmol, 1.0 equiv) in anhydrous THF (50mL) at −78° C. was added LDA (7.25 mL, 1.8 M/heptane/ethylbenzene/THF,13.05 mmol, 1.5 equiv) dropwise over a period of 2 min. The resultingdeep red-brown solution was stirred at −78° C. for 30 min. Anhydrous DMF(1.35 mL, 17.44 mmol, 2.0 equiv) was added. The resulting light brownsolution was stirred at −78° C. for 30 min. The reaction was quenched at−78° C. with HOAc (0.90 mL), warmed up to rt, diluted with EtOAc (200mL), washed with water (500 mL×1), saturated aqueous sodium bicarbonate(100 mL×1), and brine (100 mL×1). The EtOAc solution was dried oversodium sulfate and concentrated under reduced pressure. Flash columnchromatography on silica gel with 0%-15% EtOAc/hexanes yielded thedesired product S10-5 as an orange solid (2.55 g, 61%): R_(f) 0.50 (20%EtOAc/hexanes): ¹H NMR (400 MHz, CDCl₃) δ 10.26 (s, 1H), 7.39 (br s,1H), 7.30-7.42 (m, 7H), 7.23-7.30 (m, 1H), 7.07 (d, J=7.3 Hz, 2H), 4.96(s, 2H), 2.36 (d, J=2.4 Hz, 3H), 1.44 (s, 9H); MS (ESI) m/z 480.1 (M+H),calcd for C₂₇H₂₆FNO₆ 479.2.

To a solution of S10-5 (0.40 g, 0.83 mmol, 1.0 equiv) in1,2-dichloroethane (8.4 mL) was added dimethylamine (33% in EtOH, 0.57mL, 4.18 mmol, 5.0 equiv) and acetic acid (0.14 mL, 2.50 mmol, 3.0equiv). The mixture was stirred at rt for 2 hrs. Na(OAc)₃BH (0.53 g,2.50 mmol, 3.0 equiv) was added, and the reaction was stirred for 15hrs. The mixture was diluted with EtOAc (15 mL). The organic layer waswashed two times with potassium phosphate dibasic solution (preparedfrom 2 g K₂HPO₄ and 5 mL water), dried (sodium sulfate) andconcentrated.

To the above residue in DMF (8 mL) was added Boc₂O (0.24 g, 1.08 mmol,1.3 equiv), DMAP (10 mg, 0.080 mmol, 0.1 equiv) and Et₃N (0.58 mL, 4.20mmol, 5.1 equiv). The reaction was stirred at rt for 2 hrs. Sodiumhydride (60% dispersion in mineral oil, 0.18 g, 4.40 mmol, 5.3 equiv)was added, and the mixture was stirred for 2 hrs. The mixture wasquenched by brine (2 mL) and diluted with EtOAc (100 mL). The organiclayer was washed with brine (30 mL×5), dried (sodium sulfate) andconcentrated. The residue was purified by flash chromatography on silicagel, eluting with hexanes/EtOAc (5:1) to afford 0.52 g of compound 60(quant. yield): ¹H NMR (400 MHz, CDCl₃) δ 7.40-7.18 (comp, 8H),7.02-6.96 (comp, 2H), 4.96 (s, 2H), 3.37 (s, 2H), 2.37 (d, J=2.4 Hz,3H), 2.22 (s, 6H), 1.36 (s, 18H); MS (ESI) m/z 609.33 (M+H).

To a solution of i-Pr₂NH (0.27 mL, 1.93 mmol, 3.0 equiv) in THF (7 mL)was added a solution of n-BuLi (0.89 mL, 2.17 M/hexanes, 1.93 mmol, 3.0equiv) dropwise at −78° C. The reaction was allowed to warm to 0° C.,stirred at 0° C. for 25 min, and then cooled to −78° C. TMEDA (0.29 mL,1.93 mmol, 3.0 equiv) was added, and the mixture was stirred at −78° C.for 5 min. A solution of compound S10-6 (0.51 g, 0.83 mmol, 1.3 equiv)in THF (0.5 mL) was added dropwise to the LDA solution over 5 min. Onceaddition was complete, the reaction mixture was stirred at −78° C. for30 min. A solution of enone S1-9 (0.31 g, 0.64 mmol, 1.0 equiv) in THF(0.5 mL) was added dropwise over 2 min. The mixture was slowly warmed to−20° C. over 40 min and quenched by phosphate buffer (pH 7, 10 mL). Theaqueous layer was extracted with EtOAc (20 mL×3). All organic layerswere combined, dried (sodium sulfate), and concentrated. The residue waspurified by flash chromatography on silica gel, eluting withhexanes/EtOAc (20:1 to 3:1) to afford 0.56 g of compound S10-7 (87%): ¹HNMR (400 MHz, CDCl₃) δ 15.96 (s, 1H), 7.50-7.24 (comp, 10H), 5.35 (s,2H), 4.93 (d, J=9.8 Hz, 1H), 4.83 (d, J=9.8 Hz, 1H), 3.94 (d, J=12.2 Hz,1H), 3.35 (s, 2H), 3.31-3.23 (m, 1H), 3.05-2.94 (m, 1H), 2.49 (s, 6H),2.59-2.36 (comp, 3H), 2.21 (s, 6H), 2.20-2.10 (m, 1H), 1.37 (s, 9H),1.32 (s, 9H), 0.81 (s, 9H), 0.27 (s, 3H), 0.12 (s, 3H); MS (ESI) m/z997.42 (M+H).

To a solution of compound S10-7 in 1,4-dioxane (4 mL) was added HCl in1,4-dioxane (4 N, 4 mL). The mixture was stirred for 3 hrs and thenconcentrated under reduced pressure. Potassium phosphate dibasicsolution (prepared from 2 g K₂HPO₄ and 5 mL water) was added. Themixture was extracted with EtOAc (10 mL×3). All organic layers werecombined, dried (sodium sulfate) and concentrated to afford 0.45 g(quant. yield) of compound S10-8: ¹H NMR (400 MHz, CDCl₃) δ 16.15 (s,1H), 7.57-7.24 (comp, 10H), 5.35 (s, 2H), 4.90 (d, J=11.9 Hz, 1H), 4.82(d, J=11.9 Hz, 1H), 3.97 (d, J=10.4 Hz, 1H), 3.50 (s, 2H), 3.17-3.09 (m,1H), 3.03-2.93 (m, 1H), 2.48 (s, 6H), 2.18 (s, 6H), 2.57-2.08 (comp,4H), 0.82 (s, 9H), 0.27 (s, 3H), 0.13 (s, 3H); MS ESI) m/z 797.36 (M+H).

To a solution of compound S10-8 (14 mg, 0.020 mmol, 1.0 equiv) and Et₃N(37 μL, 0.26 mmol, 13 equiv) in dichloromethane (2 mL) was added asolution of AcCl (2.2 μL, 0.030 mmol, 1.5 equiv) in dichloromethane (0.4mL). The reaction was stirred at rt for 1 h, quenched by MeOH (0.3 mL),and then concentrated under reduced pressure. The crude product waspurified by preparative reverse phase HPLC on a Waters Autopurificationsystem using a Sunfire Prep C18 OBD column [5 μm, 19×50 mm; flow rate,20 mL/min; Solvent A: H₂O with 0.1% HCO₂H; Solvent B: CH₃CN with 0.1%HCO₂H; injection volume: 2.0 mL (CH₃CN); gradient: 30→70% B over 10 min;mass-directed fraction collection]. Fractions containing the desiredproduct, eluting at 6.2-7.0 min, were collected and freeze-dried to give14 mg of 510-9-1 (96%): ¹H NMR (400 MHz, CDCl₃) δ 15.98 (s, 1H),7.54-7.24 (comp, 10H), 5.35 (s, 2H), 4.96-4.83 (m, 2H), 3.94 (d, J=9.8Hz, 1H), 3.47 (s, 2H), 3.26-3.18 (m, 1H), 3.05-2.95 (m, 1H), 2.49 (s,6H), 2.23 (s, 6H), 2.60-2.10 (comp, 4H), 2.00 (s, 3H), 0.82 (s, 9H),0.27 (s, 3H), 0.13 (s, 3H); MS (ESI) m/z 839.34 (M+H).

To a solution of S10-9-1 (14 mg, 0.020 mmol) in 1,4-dioxane (3 mL) wasadded a solution of HF (0.3 mL of 48-50% solution in water). The mixturewas stirred for 4 hrs and then quenched by potassium phosphate dibasicsolution (prepared from 2 g K₂HPO₄ and 5 mL water). The mixture wasextracted with EtOAc (5 mL×3). All organic layers were combined, dried(sodium sulfate) and concentrated.

To the above residue in MeOH/dioxane solution (1:1, 4 mL) was added Pd—C(10 mg, 10 wt %) and HCl in MeOH (0.5 N, 0.3 mL). The reaction wasbubbled with H₂ (balloon) at 25° C. for 30 min. The mixture was filteredthrough a small Celite plug. The filtrate was concentrated to yield thecrude product. The crude product was purified by preparative reversephase HPLC on a Waters Autopurification system using a PhenomenexPolymerx 10μ RP-□ 100A column [10 μm, 150×21.20 mm; flow rate, 20mL/min; Solvent A: 0.05 N HCl/water; Solvent B: CH₃CN injection volume:2.1 mL (0.05 N HCl/water); gradient: 0→100% B over 10 min; mass-directedfraction collection]. Fractions containing the desired product, elutingat 5.1-5.3 min, were collected and freeze-dried to yield 1 mg ofS10-10-1 (11% for 2 steps): ¹H NMR (400 MHz, CD₃OD) δ4.36 (s, 2H), 4.10(s, 1H), 3.05 (s, 3H), 2.96 (s, 3H), 2.94 (s, 6H), 3.22-2.88 (comp, 3H),2.45-2.34 (m, 1H), 2.28 (s, 3H), 2.28-2.21 (m, 1H), 1.73-1.61 (m, 1H);MS (ESI) m/z 547.22 (M+H).

S10-10-2 was prepared according to the procedure for the preparation ofS10-10-1: ¹H NMR (400 MHz, CD₃OD) δ 4.30 (s, 2H), 4.09 (s, 1H), 3.05 (s,3H), 2.96 (s, 3H), 2.94 (s, 6H), 3.22-2.90 (comp, 3H), 2.46-2.36 (m,1H), 2.29-2.20 (comp, 1H), 1.74-1.62 (m, 1H), 1.39 (s, 9H); MS (ESI) m/z589.18 (M+H).

S10-10-3 was prepared according to the procedure for the preparation ofS10-10-1: ¹H NMR (400 MHz, CD₃OD) δ 4.49 (s, 2H), 4.47 (s, 2H), 4.11 (s,1H), 3.86-3.76 (m, 2H), 3.38-3.32 (m, 2H), 3.04 (s, 3H), 2.99 (s, 3H),2.96 (s, 6H), 3.24-2.90 (comp, 3H), 2.45-2.36 (m, 1H), 2.30-2.00 (comp,5H), 1.72-1.60 (m, 1H); MS (ESI) m/z 616.25 (M+H).

To a solution of compound S10-8 (59 mg, 0.070 mmol, 1.0 equiv) and Et₃N(0.15 mL, 1.11 mmol, 16 equiv) in dichloromethane (2 mL) was addedmethanesulfonic anhydride (28 mg, 0.30 mmol, 4.3 equiv). The reactionwas stirred at rt for 1 h. The mixture was purified by flashchromatography on silica gel, eluting with hexanes/EtOAc (20:1 to 2:1)to afford 10 mg of compound S10-9-2 (15%/o): ¹H NMR (400 MHz, CDCl₃) δ16.01 (s, 1H), 7.54-7.24 (comp, 10H), 5.35 (s, 2H), 4.96 (s, 2H), 3.93(d, J=10.4 Hz, 1H), 3.68 (d, J=13.7 Hz, 1H), 3.62 (d, J=13.7 Hz, 1H),3.24-3.17 (m, 1H), 3.00 (s, 3H), 3.06-2.98 (m, 1H), 2.48 (s, 6H), 2.27(s, 6H), 2.59-2.11 (comp, 4H), 0.83 (s, 9H), 0.27 (s, 3H), 0.14 (s, 3H);MS (ESI) m/z 875.38 (M+H).

S10-10-4 was prepared from S10-9-2 according to the procedure for thepreparation of S10-10-1: ¹H NMR (400 MHz, CD₃OD) δ 4.67 (d, J=13.4 Hz,1H), 4.63 (d, J=13.4 Hz, 1H), 4.10 (s, 1H), 3.11 (s, 3H), 3.04 (s, 3H),2.99 (s, 3H), 2.96 (s, 6H), 3.24-2.90 (comp, 3H), 2.46-2.35 (m, 1H),2.29-2.22 (comp, 1H), 1.72-1.61 (m, 1H); MS (ESI) m/z 583.10 (M+H).

To a solution of compound S10-8 (27 mg, 0.030 mmol, 1.0 equiv) andacetic acid (6 μL, 0.10 mmol, 3.3 equiv) in 1,2-dichloroethane (1 mL)was added isobutyraldehyde (16 μL, 0.17 mmol, 5.6 equiv). The mixturewas stirred at rt for 2 hrs. Na(OAc)₃BH (22 mg, 0.10 mmol, 3.3 equiv)was added, and the reaction was stirred for 3 hrs. Another portion ofNa(OAc)₃BH (22 mg, 0.10 mmol, 3.3 equiv) was added, and the reaction wasstirred for another 3 hrs. The mixture was diluted with EtOAc (10 mL).The organic layer was washed four times with potassium phosphate dibasicsolution (prepared from 0.5 g K₂HPO₄ and 1 mL water), dried (sodiumsulfate) and concentrated. The residue was purified by flashchromatography on silica gel, eluting with hexanes/EtOAc (20:1 to 10:1)to afford 23 mg of compound S10-9-3 (80%): ¹H NMR (400 MHz, CDCl₃) δ16.27 (s, 1H), 7.55-7.24 (comp, 10H), 5.83-5.56 (br, 1H), 5.35 (s, 2H),4.89 (d, J=10.4 Hz, 1H), 4.81 (d, J=10.4 Hz, 1H), 3.97 (d, J=10.4 Hz,1H), 3.48 (s, 2H), 3.22-3.07 (comp, 3H), 2.97-2.87 (m, 1H), 2.48 (s,6H), 2.55-2.30 (comp, 3H), 2.23 (s, 6H), 2.14-2.06 (m, 1H), 1.78-1.66(m, 1H), 0.89 (d, J=1.8 Hz, 3H), 0.87 (d, J=1.8 Hz, 3H), 0.82 (s, 9H),0.26 (s, 3H), 0.13 (s, 3H); MS (ESI) m/z 853.39 (M+H).

S10-10-5 was prepared from S10-9-3 according to the procedure for thepreparation of S10-10-1: ¹H NMR (400 MHz, CD₃OD) δ 4.51 (s, 2H), 4.08(s, 1H), 3.03 (s, 3H), 2.96 (s, 3H), 2.90 (s, 6H), 3.21-2.82 (comp, 5H),2.36-2.25 (m, 1H), 2.25-2.17 (m, 1H), 1.93-1.81 (m, 1H), 1.69-1.58 (m,1H), 1.04 (d, J=2.4 Hz, 3H), 1.02 (d, J=2.4 Hz, 3H); MS (ESI) m/z 561.18(M+H).

S10-10-6 was prepared from S10-8 via HF treatment followed byhydrogenation according to the procedure for the preparation ofS10-10-1: ¹H NMR (400 MHz, CD₃OD) δ 4.42 (s, 2H), 4.08 (s, 1H), 3.14(dd, J=21.4, 4.9 Hz, 1H), 3.03 (s, 3H), 2.96 (s, 3H), 2.92 (s, 6H),3.09-2.88 (comp, 2H), 2.26-2.17 (comp, 2H), 1.66-1.54 (m, 1H); MS (ESI)m/z 505.12 (M+H).

Example 11 Synthesis of Compounds Via Scheme 11

The following compounds were prepared according to Scheme 11.

Compound S1-7 (0.44 g, 1.00 mmol, 1.0 equiv) was dissolved in1,2-dichloroethane (5 mL) and pyrrolidine (0.25 mL, 3.00 mmol, 3.0equiv) was added via a syringe followed by acetic acid (0.17 mL, 3.00mmol, 3.0 equiv) under a nitrogen atmosphere. After stirring at rt for 1h, sodium triacetoxyborohydride (0.32 g, 1.50 mmol, 1.5 equiv) was addedto reaction mixture. The reaction was stirred at rt overnight. Another1.0 equiv of reagents were added. LC/MS indicated that the startingmaterial was consumed after stirring for another 2 hrs. The reactionmixture was diluted with dichloromethane, washed with NaHCO₃ (saturatedaqueous solution, 3×20 mL) and brine, dried over sodium sulfate,filtered, and concentrated under reduced pressure to give crude compoundS11-1-1 (0.53 g), which was used without further purification:

¹H NMR (400 MHz, CDCl₃) δ 10.37 (s, 1H), 7.53-7.49 (m, 2H), 7.40-7.33(m, 5H), 7.26 (t, J=7.8 Hz, 1H), 7.09-7.05 (m, 2H), 5.13 (s, 2H), 3.94(d, J=2.7 Hz, 2H), 2.66 (br, s, 2H), 2.35 (d, J=2.3 Hz, 3H), 1.82-1.76(m, 2H).

Isopropylmagnesium chloride/lithium chloride (0.30 mL, 1.2 M/THF, 0.36mmol, 1.8 equiv) was added to compound S11-1-1 (0.10 g, 0.20 mmol, 1.0equiv) in THF (2 mL) under a nitrogen atmosphere at −78° C. Theresulting solution was warmed up to rt and stirred for another 45 min.After the solution was cooled down to −78° C., TsN₃ (91 mg, 0.50 mmol,2.5 equiv) in THF (1 mL) was added slowly via a syringe. The reactionwas warmed to −40° C. and stirred for another 45 min. LC/MS indicatedthat the starting materials was consumed and the product present. Thereaction mixture was allowed to slowly warm to −20° C. Saturated aqueoussodium bicarbonate (10 mL) was added. The resulting mixture wasextracted with dichloromethane (3×15 mL), and the combined extracts weredried over sodium sulfate, filtered, and concentrated under reducedpressure to yield crude S11-2-1 (0.15 g) as a pale yellow oil.

Compound S11-2-1 (crude, 0.15 g, 0.20 mmol, 1.5 equiv) and enone S1-9(64 mg, 0.13 mmol, 1.0 equiv) were dissolved in 2 mL dry THF under anitrogen atmosphere in a flame dried schenck flask at −78° C. LHMDS(0.40 mL, 1.0 M/THF, 0.40 mmol, 3.1 equiv) was added slowly via asyringe. A red-orange color appeared. The reaction was warmed to −30° C.and stirred for another 15 min. Phosphate buffer (pH 7, 10 mL) wasadded, followed by the addition of 20 mL saturated aqueous ammoniumchloride. The resulting mixture was extracted with dichloromethane (3×15mL), and the combined extracts were dried over sodium sulfate, filtered,and concentrated under reduced pressure. The red-orange oil was purifiedby preparative reverse phase HPLC purification on a WatersAutopurification system using a Sunfire Prep C18 OBD column [5 μm, 19×50mm; flow rate, 20 mL/min; Solvent A: H₂O with 0.1% HCO₂H; Solvent B:CH₃CN with 0.1% HCO₂H; injection volume: 4.0 mL (CH₃CN); gradient: 0→50%B over 15 min; mass-directed fraction collection]. Fractions containingthe desired product were collected and concentrated at rt to remove mostof the acetonitrile. The resulting mostly aqueous solution was extractedwith EtOAc. The EtOAc extract was dried (sodium sulfate) andconcentrated to give 20 mg of compound S11-3-1 (12% for 3 steps).

Aqueous HF (0.3 mL, 48-50%) was added to a CH₃CN solution (1.0 mL) ofS11-3-1 (20 mg) in a plastic vial at 25° C. The reaction was stirred at25° C. for 18 hrs. The reaction solution was poured into an aqueoussolution (10 mL) of K₂HPO₄ (2 g). The mixture was extracted with EtOAc(3×15 mL). The combined EtOAc extracts were dried over sodium sulfateand concentrated to give the crude intermediate (18 mg).

Pd—C (5 mg, 10 wt %) was added to a MeOH solution (2 mL) of the abovecrude intermediate. HCl in MeOH (0.5 N, 0.5 mL) was added. The reactionwas stirred under H₂ (balloon) at 25° C. for 45 min and filtered througha pad of Celite. The filtrate was concentrated to afford the crudeproduct, which was purified by reverse phase HPLC on a Polymerx 10μRP-γ100 R column [30×21.20 mm, 10 micron, solvent A: 0.05 N HCl, solventB: CH₃CN, sample in 2.0 mL (0.05 N HCl), gradient elution with 0→70% Bover 15 min, mass-directed fraction collection]. Fractions containingthe desired product were collected and freeze-dried, yielding 8 mg ofthe desired product S1-4-1 as a yellow solid (65% for two steps): ¹H NMR(400 MHz, CD₃OD) δ 4.64 (s, 2H), 4.12 (s, 1H), 3.68 (m, 2H), 3.32 (m,2H), 3.05 (s, 3H), 2.96 (s, 3H), 3.27-2.97 (m, 3H), 2.45 (m, 1H),2.30-2.13 (m, 3H), 2.13-2.00 (m, 2H), 1.69-1.59 (m, 1H); MS (ESI) m/z541.27 (M+H).

Example 12 Synthesis of Compounds Via Scheme 12

The following compounds were prepared according to Scheme 12.

iPrMgCl.LiCl (4.00 mL, 1.2 M/THF, 4.80 mmol, 2.0 equiv) was added to aTHF solution (12 mL) of S1-6 (1.00 g, 2.40 mmol,) at 0° C. The reactionwas stirred at 0° C. for 30 min. (PhSO₂)₂NF (1.50 g, 4.80 mmol, 2.0equiv) was added to the reaction mixture. The reaction was stirred at 0°C. for 30 min and allowed to warm to 25° C. over 1 h, quenched bysaturated aqueous NH₄Cl, and extracted with EtOAc. The EtOAc extract wasdried (sodium sulfate) and concentrated to give the crude product. Flashchromatography on silica gel (30:1 hexanes/EtOAc) yielded 0.50 g ofcompound S12-1 (59%).

n-BuLi (6.50 mL, 1.6 M/hexanes, 10.40 mmol, 1.5 equiv) was added to aTHF solution (15 mL) of diisopropylamine (1.50 mL, 10.40 mmol, 1.5equiv) at 0° C. The reaction was stirred at 0° C. for 30 min and cooledto −78° C. To the mixture was added a THF solution (15 mL) of S12-1(2.29 g, 6.47 mmol, 1.0 equiv). The reaction was stirred at −78° C. for20 min and DMF (1.50 mL, 19.40 mmol, 3.0 equiv) was added. The reactionwas allowed to warm to 25° C. over 1 h and quenched by saturated aqueousNH₄Cl. The resulting mixture was extracted with EtOAc. The EtOAc extractwas dried over sodium sulfate and concentrated. Flash chromatography onsilica gel (10:1 hexanes/EtOAc) yielded 1.70 g of compound S12-2 (69%).

Pyrrolidine (65 μL, 0.79 mmol, 5.0 equiv), Na(OAc)₃BH (68 mg, 0.32 mmol,2.0 equiv), and HOAc (47 μL) were added to a dichloromethane solution (3mL) of S12-2 (60 mg, 0.16 mmol, 1.0 equiv). The reaction was stirred at25° C. for 1 h and quenched by H₂O. The resulting mixture was extractedwith dichloromethane. The dichloromethane extract was dried (sodiumsulfate) and concentrated to give crude S12-3-1.

A THF solution (1 mL) of crude S12-3-1 (0.14 mmol, 1.7 equiv) was addedto a THF solution (1 mL) of LDA (0.17 mL, 1.8M/THF/heptane/ethylbenzene, 0.31 mmol, 3.7 equiv) and TMEDA (84 μL, 0.56mmol, 6.7 equiv). The reaction was stirred at −78° C. for 10 min. A THFsolution (1 mL) of enone S1-9 (40 mg, 0.084 mmol, 1.0 equiv) was addedto the reaction at −78° C. The reaction was stirred at −78° C. for 30min and allowed to warm to 25° C. over 1 h, quenched by saturatedaqueous NH₄Cl, and extracted with EtOAc. The EtOAc extract was dried(sodium sulfate) and concentrated. The crude product was purified bypreparative reverse phase HPLC on a Waters Autopurification system usinga Sunfire Prep C18 OBD column [5 μm, 19×50 mm; flow rate, 20 mL/min;Solvent A: H₂O with 0.1% HCO₂H; Solvent B: CH₃CN with 0.1% HCO₂H;injection volume: 4.0 mL (CH₃CN); gradient: 50→100% B over 15 min;mass-directed fraction collection]. Fractions containing the desiredproduct were collected and concentrated at 25° C. to remove most of theacetonitrile. The resulting aqueous solution was extracted with EtOAc,and the EtOAc extract was dried (sodium sulfate) and concentrated togive 16 mg of S12-4-1 (23%).

Aqueous HF (0.5 mL, 48-50%) was added to a CH₃CN solution (2 mL) ofS12-4-1 (16 mg, 0.019 mmol) in a polypropylene tube at 25° C. Thereaction was stirred at 25° C. for 18 hrs. The resulting mixture waspoured into an aqueous solution of K₂HPO₄ (4 g, dissolved in 30 mLwater). The mixture was extracted with EtOAc, and the EtOAc extract wasdried (sodium sulfate) and concentrated to yield the crude intermediate.

Pd—C (8 mg, 10 wt %) was added to a HCl/MeOH solution (0.5N, 2 mL) ofthe above crude product. The reaction was purged with hydrogen andstirred under H₂ (balloon) at 25° C. for 4 hrs. The reaction mixture wasfiltered through a small Celite plug. The filtrate was concentrated toyield the crude product, which was purified by preparative reverse phaseHPLC on a Waters Autopurification system using a Phenomenex Polymerx 10μRP-γ 100A column [10 μm, 150×21.20 mm; flow rate, 20 ml/min; Solvent A:0.05 N HCl/water; Solvent B: CH₃CN; injection volume: 4.0 mL (0.05 NHCl/water); gradient: 0→70% B over 7 min, 70→100% over 3 min, and 100%over 5 min; mass-directed fraction collection]. Fractions containing thedesired product were collected and freeze-dried to yield 2 mg ofcompound S12-5-1: ¹H NMR (400 MHz, CD₃OD) δ 4.58 (s, 2H), 4.10 (s, 1H),3.71-3.67 (m, 2H), 3.30-2.92 (m, 5H), 3.05 (s, 3H), 2.97 (s, 3H),2.41-2.32 (m, 1H), 2.29-2.15 (m, 3H), 2.10-1.98 (m, 2H), 1.72-1.60 (m,1H); MS (ESI) m/z 534.23 (M+H).

The following compounds were prepared similarly to S12-5-1.

S12-5-2: ¹H NMR (400 MHz, CD₃OD) δ 4.43 (s, 2H), 4.08 (s, 1H), 3.29-2.92(m, 3H), 3.04 (s, 3H), 3.00 (s, 2H), 2.96 (s, 3H), 2.39-2.28 (m, 1H),2.26-2.19 (m, 1H), 1.70-1.59 (m, 1H), 1.06 (s, 9H); MS (ESI) m/z 550.16(M+H).

S12-5-3: ¹H NMR (400 MHz, CD₃OD) δ 4.32 (s, 2H), 4.10 (s, 1H), 3.24-2.93(m, 3H), 3.04 (s, 3H), 2.95 (s, 3H), 2.39-2.20 (m, 2H), 1.70-1.58 (m,1H), 1.48 (s, 9H), MS (ESI) m/z 536.24 (M+H).

S12-5-4: ¹H NMR (400 MHz, CD₃OD) δ 4.19 (s, 2H), 4.11 (s, 1H), 3.25-2.95(m, 3H), 3.06 (s, 3H), 2.96 (s, 3H), 2.80 (s, 3H), 2.42-2.21 (m, 2H),1.71-1.58 (m, 1H), 1.58 (s, 9H); MS (ESI) m/z 550.26 (M+H).

Example 13 Synthesis of Compounds Via Scheme 13

The following compounds were prepared according to Scheme 13.

A solution of benzoic acid S13-1 (5.00 g, 26.60 mmol, 1.0 equiv) in THF(40 mL) was added dropwise to a solution of s-BuLi (41.76 mL, 1.4M/cyclohexane, 58.50 mmol, 2.2 equiv) and TMEDA (8.77 mL, 58.50 mmol,2.2 equiv) in THF (40 mL) at −78° C. via a cannula over 30 min. Theresulting red-orange thick reaction mixture was stirred at −78° C. for 2hrs, slowly changing to a yellow brownish suspension. Iodomethane (8.30mL, 133.00 mmol, 5.0 equiv) was added at −78° C. slowly. The resultingyellow suspension was then stirred at rt for 30 min. Water (50 mL) wasadded, and the resulting mixture was concentrated to remove most of theTHF. Aqueous NaOH (40 mL, 6 N) was added, and the resulting mixture wasextracted with methyl I-butyl ether (2×60 mL). The combined organicphases were extracted with aqueous NaOH (40 mL, 3 N). The combinedaqueous layers were acidified with 6 N HCl (−65 mL) to pH 1, andextracted with EtOAc (120 mL, then 80 mL). The combined EtOAc extractswere dried over magnesium sulfate, filtered and concentrated to affordcrude S13-2 as an orange solid (S13-2:region-isomer:S13-1=˜1.2:0.8:1 by¹H NMR).

The above crude product was dissolved in dry dichloromethane (100 mL).Oxalyl chloride (2.78 mL, 31.89 mmol, 1.2 equiv) was added, followed bya few drops of DMF. The reaction mixture was stirred at rt for 1 h,concentrated and further dried under high vacuum. The residue wasre-dissolved in dry dichloromethane (100 mL). Phenol (2.75 g, 29.26mmol, 1.1 equiv), triethylamine (7.40 mL, 53.20 mmol, 2.0 equiv), andDMAP (0.10 g, 0.82 mmol, 0.03 equiv) were added. The reaction mixturewas stirred at rt for 1 h. The solvent was evaporated and the residuewas dissolved in EtOAc (200 mL). The organic layer was washed with 1 NHCl (60 mL), 1 N NaOH (70 mL), water (50 mL) and brine (60 mL), driedover anhydrous magnesium sulfate, filtered, and concentrated. Theresidue was purified by flash column chromatography (1-4% EtOAc/hexanes)to afford the desired product S13-3 as a white solid (1.39 g, 19% overtwo steps): ¹H NMR (400 MHz, CDCl₃) δ 7.47-7.43 (m, 2H), 7.31-7.29 (m,1H), 7.26-7.24 (m, 2H), 6.67 (dd, J=6.0, 11.4 Hz, 1H), 3.84 (s, 3H),2.41 (s, 3H); MS (ESI) m/z 277.22 (M−H).

A solution of BBr₃ in dichloromethane (6.00 mL, 1.0 M, 6.00 mmol, 1.2equiv) was added slowly to compound S13-3 (1.39 g, 5.00 mmol, 1.0 equiv)in dichloromethane (25 mL) at −78° C. The resulting orange solution wasallowed to warm to 0° C. in 30 min and kept at that temperature for 10min [monitored by LC-MS or TLC (product is slightly more polar)].Saturated aqueous NaHCO₃ was added. The mixture was stirred at rt for 5min and dichloromethane was evaporated. The residue was extracted withEtOAc (60 mL, then 20 mL). The organic extracts were combined, driedover anhydrous magnesium sulfate, filtered, and concentrated to give thecrude intermediate (1.27 g) as a waxy solid: ¹H NMR (400 MHz, CDCl₃) δ11.07 (s, 1H), 7.47-7.44 (m, 2H), 7.34-7.30 (m, 1H), 7.19-7.17 (m, 2H),6.69 (dd, J=6.7, 11.0 Hz, 1H), 2.63 (d, J=3.0 Hz, 3H); MS (ESI) m/z263.20 (M−H).

Benzylbromide (0.24 mL, 2.04 mmol, 1.2 equiv), K₂CO₃ powder (0.47 g,3.41 mmol, 2.0 equiv) and KI (14 mg, 0.085 mmol, 0.05 equiv) were addedto the above crude intermediate (0.45 g, 1.70 mmol, 1.0 equiv) inacetone (3.4 mL). The mixture was heated at reflux for 4.5 hrs, cooledto it, and diluted with EtOAc (50 mL) and water (30 mL). The organicphase was separated, washed with brine, dried over magnesium sulfate,and concentrated. The residue was purified by flash columnchromatography (1-4% EtOAc/hexanes) to afford the desired product S13-4as a crystalline white solid (0.50 g, 79% over 2 steps): ¹H NMR (400MHz, CDCl₃) δ 7.45-7.31 (m, 7H), 7.28-7.24 (m, 1H), 7.10-7.08 (m, 2H),6.71 (dd, J=6.1, 11.6 Hz, 1H), 5.10 (s, 2H), 2.41 (d, J=1.8 Hz, 3H); MS(ESI) m/z 353.21 (M−H).

A solution of compound S13-4 (0.38 g, 1.08 mmol, 1.0 equiv) in THF (4mL) was added via a cannula dropwise to a solution of LDA (1.01 mL, 1.62mmol, 1.5 equiv) and TMEDA (0.24 mL, 1.62 mmol, 1.5 equiv) in THF (6 mL)at −78° C. The resulting red orange solution was stirred at −78° C. for5 min. DMF (0.17 mL, 2.16 mmol, 2.0 equiv) was added. The reaction wasstirred at −78° C. for 1 h. Saturated aqueous NH₄Cl (30 mL) was addeddropwise to the reaction mixture at −78° C. The resulting mixture wasthen warmed up to rt and extracted with EtOAc (60 mL, then 20 mL). Thecombined EtOAc extracts were dried (sodium sulfate), filtered andconcentrated. The residue was purified by flash column chromatography(1-20% EtOAc/hexanes) to afford the desired product S13-5 as a colorlessoil (0.26 g, 62%): ¹H NMR (400 MHz, CDCl₃) δ 7.42-7.35 (m, 7H),7.29-7.25 (m, 1H), 7.06-7.04 (m, 2H), 5.10 (s, 2H), 2.48 (d, J=2.4 Hz,3H); MS (ESI) m/z 381.24 (M−H).

t-BuNH₂ (96 μL, 0.91 mmol, 5.0 equiv) was added to a mixture of aldehydeS13-5 (69 mg, 0.18 mmol, 1.0 equiv) and sodium sulfate in toluene (1mL). The resulting light greenish reaction mixture was stirred at rtovernight. The solids were filtered off. The filtrate was concentratedunder reduced pressure to afford the crude imine, which was useddirectly in the next step.

A solution of the above imine (0.18 mmol, 1.0 equiv) in THF (1.5 mL) wasadded via a cannula dropwise to a solution of LDA (0.16 mL, 0.26 mmol,1.4 equiv) and TMEDA (38 μL, 0.26 mmol, 1.4 equiv) in THF (4 mL) at −78°C. The resulting red-purple reaction mixture was then stirred at −78° C.for 5 min. A solution of enone S1-9 (70 mg, 0.15 mmol, 0.8 equiv) in THF(1.5 mL) was added via a cannula. The resulting dark purple solution wasstirred at −78° C. for 8 min, and LHMDS solution (0.18 mL, 1.0 M/THF,0.18 mmol, 1.0 equiv) was added. The reaction mixture was warmed to −10°C. over 1 h 25 min, quenched by saturated aqueous NH4Cl (20 mL), andextracted with EtOAc (50 mL, then 20 mL). The combined EtOAc extractswere dried (sodium sulfate), filtered and concentrated. The residue waspurified by a preparative reverse phase HPLC on a WatersAutopurification system using a Sunfire Prep C18 OBD column [5 μm, 19×50mm; flow rate, 20 ml/min; Solvent A: H₂O with 0.1% HCO₂H; Solvent B:CH₃CN with 0.1% HCO₂H; injection volume: 4.0 mL (CH₃CN); gradient:80→100% B in A over 10 min; mass-directed fraction collection].Fractions containing the desired product were collected and concentratedat rt to yield the desired product S13-7 (23 mg, 20%): ¹H NMR (400 MHz,CDCl₃) δ 15.85 (br s, 1H), 10.10 (s, 1H), 7.70-7.68 (m, 1H), 7.52-7.49(m, 3H), 7.40-7.31 (m, 6H), 5.36 (s, 2H), 5.06, 4.98 (ABq, J=10.4 Hz,2H), 3.91 (d, J=11.0 Hz, 1H), 3.34 (dd, J=4.3, 15.9 Hz, 1H), 3.07-3.00(m, 1H), 2.61-2.58 (m, 1H), 2.54-2.34 (m, 2H), 2.50 (s, 6H), 2.20-2.16(m, 1H), 0.82 (s, 9H), 0.28 (s, 3H), 0.14 (s, 3H); MS (ESI) m/z 771.53(M+H).

Neopentylamine (17 μL, 0.15 mmol, 5.0 equiv), acetic acid (8 μL, 0.15mmol, 5.0 equiv) and sodium triacetoxyborohydride (12 mg, 0.058 mmol,2.0 equiv) were added sequentially to a solution of aldehyde S13-7 (23mg, 0.029 mmol, 1.0 equiv) in 1,2-dichloroethane (1 mL) at 23° C. Afterstirring for 1 h, the reaction mixture was quenched by the addition ofsaturated aqueous sodium bicarbonate and pH 7 phosphate buffer (1:1, 15mL) and extracted with dichloromethane (50 mL). The organic phase wasdried over anhydrous sodium sulfate, filtered, and concentrated toafford crude S13-8-1, which was used directly in the next step.

Aqueous HF (48-50%, 0.3 mL) was added to a solution of compound S13-8-1in acetonitrile (0.7 mL) in a polypropylene reaction vessel at 23° C.The reaction was stirred vigorously at 23° C. overnight and poured intoaqueous K₂HPO₄ (3.6 g dissolved in 20 mL water). The mixture wasextracted with EtOAc (2×25 mL). The combined organic extracts were driedover anhydrous sodium sulfate, filtered, and concentrated. The residuewas used directly in the next step without further purification.

Pd—C (10 wt %, 7 mg) was added into a solution of the above crudeproduct in a mixture of HCl/MeOH (0.5 N, 0.12 mL, 2.0 equiv) and MeOH (2mL) at 23° C. The reaction vessel was sealed and purged with hydrogen bybriefly evacuating the flask followed by flushing with hydrogen gas (1atm). The reaction was stirred at 23° C. for 30 min. The reactionmixture was then filtered through a small Celite pad. The filtrate wasconcentrated. The residue was purified by a preparative reverse phaseHPLC on a Waters Autopurification system using a Phenomenex Polymerx 10μRP-□ 100A column [10 μm, 150×21.20 mm; flow rate, 20 mL/min; Solvent A:0.05 N HCl/water; Solvent B: CH₃CN; injection volume: 3.0 mL (0.05 NHCl/water); gradient: 5→40% B over 15 min; mass-directed fractioncollection]. Fractions containing the desired product, eluting at12.6-13.1 min, were collected and freeze-dried to yield compound S13-9-1(4 mg, 23% for 3 steps): ¹H NMR (400 MHz, CD₃OD) δ 4.38 (s, 2H), 4.10(s, 1H), 3.11-2.96 (m, 11H), 2.39 (t, J=15.1 Hz, 1H), 2.26-2.23 (m, 1H),1.70-1.60 (m, 1H), 1.07 (s, 9H); MS (ESI) m/z 550.40 (M+H).

S13-9-2 was prepared similarly: ¹H NMR (400 MHz, CD₃OD) δ 4.31 (s, 2H),4.11 (s, 1H), 3.57-2.50 (hept, J=6.4 Hz, 1H), 3.04-2.96 (m, 9H), 2.39(t, J=15.1 Hz, 1H), 2.27-2.24 (m, 1H), 1.70-1.60 (m, 1H), 1.43 (t, J=6.4Hz, 6H); MS (ESI) m/z 522.41 (M+H).

Example 14 Synthesis of Compounds Via Scheme 14

The following compounds were prepared according to Scheme 14.

To compound S1-1 (5.00 g, 29.38 mmol, 1.0 equiv) in sulfuric acid (10mL) and trifluoroacetic acid (20 mL) at rt was added NBS (5.75 g, 32.30mmol, 1.1 equiv). The pale solution was stirred at rt for 3 hrs. Theresulting pale suspension was carefully poured onto 500 g crushed ice.The mixture was extracted with EtOAc (200 mL×1, 100 mL×3). The EtOAcextracts were combined, dried over sodium sulfate, and concentratedunder reduced pressure. The light yellow residue was suspended inminimum dichloromethane. The solid was collected, washed with colddichloromethane (5 mL×3), and dried under vacuum overnight to yield thedesired product S14-1 as a white crystalline solid (5.49 g, 75%): R_(f)0.55 (0.5% HOAc/EtOAc); ¹H NMR (400 MHz, CDCl₃) δ 7.74-7.77 (m, 1H),7.24-7.55 (m, 1H), 4.01 (s, 3H); MS (ESI) m/z 247.1 (M−H), calcd forCsH₆BrFO₃ 248.0.

To compound S14-1 (0.25 g, 1.00 mmol, 1.0 equiv) in anhydrous THF (5 mL)at −78° C. was added TMEDA (0.75 mL, 5.00 mmol, 5.0 equiv) and LTMP(4.00 mmol, freshly prepared, in 4 mL THF) dropwise. The cloudy deep redsolution was stirred at −78° C. for 30 min. Iodomethane (0.31 mL, 5.00mmol, 5.0 equiv) was added dropwise at −78° C. The resulting palesuspension was allowed to warm to rt and was stirred overnight. AqueousHCl (1 N) was added to the reaction until pH 1-2. The mixture wasextracted with EtOAc (100 mL×1, 20 mL×3). The EtOAc extracts werecombined, dried over sodium sulfate, and concentrated under reducedpressure to afford crude S14-2 as an orange solid (0.30 g)

The compound S14-2 was dissolved in dry dichloromethane (10 mL).Anhydrous DMF (2 drops) and oxalyl chloride (0.43 mL, 5.00 mmol, 5.0equiv) were added dropwise at rt. The yellow solution was stirred at rtfor 30 min and concentrated under reduced pressure. The residue wasredissolved in dry dichloromethane (10 mL). Phenol (0.14 g, 1.50 mmol,1.5 equiv), DIEA (0.70 mL, 4.00 mmol, 4.0 equiv), and DMAP (12 mg, 0.10mmol, 0.1 equiv) were added. The reaction was stirred at rt overnight,diluted with saturated aqueous sodium bicarbonate (50 mL), and extractedwith dichloromethane (50 mL×3). The dichloromethane extracts werecombined, dried over sodium sulfate, and concentrated under reducedpressure. Flash column chromatography on silica gel using 0% to 5%EtOAc/hexanes yielded the desired product S14-3 as a pale oil (0.13 g,37%, 2 steps): R_(f) 0.70 (10% EtOAc/hexanes); ¹H NMR (400 MHz, CDCl₃) δ7.40-7.50 (m, 2H), 7.16-7.23 (m, 3H), 3.94 (s, 3H), 2.38 (s, 3H), 2.32(s, 3H); MS (ESI) m/z 351.1 (M−H), calcd for C₁₆H₁₄BrFO₃ 352.0.

Compound S14-3 (0.13 g, 0.37 mmol, 1.0 equiv) was dissolved in anhydrousdichloromethane (4 mL) and the solution was cooled to −78° C. BBr₃ (0.93mL, 1.0 M/dichloromethane, 0.93 mmol, 2.5 equiv) was added dropwise. Theorange-brown solution was warmed to −10° C. with stirring over a periodof 2 hrs. The reaction was quenched by saturated aqueous sodiumbicarbonate (20 mL) and extracted with EtOAc (20 mL×3). The extractswere combined, dried over sodium sulfate, and concentrated under reducedpressure to yield crude S14-4 as a pale solid (0.13 g).

Phenol S14-4 was dissolved in dichloromethane. Di-t-butyl dicarbonate(0.12 g, 0.56 mmol, 1.5 equiv), DIEA (0.13 mL, 0.74 mmol, 2.0 equiv),and DMAP (5 mg, 0.040 mmol, 0.1 equiv) were added. The reaction wasstirred at rt overnight and concentrated under reduced pressure. Flashcolumn chromatography on silica gel using 0% to 2% EtOAc/hexanes yieldedthe desired compound S14-5 as a white solid (0.14 g, 88%, 2 steps):R_(f) 0.25 (3% EtOAc/hexanes); ¹H NMR (400 MHz, CDCl₃) δ 77.40-7.49 (m,2H), 7.18-7.32 (m, 3H), 2.42 (d, J=3.0 Hz, 3H), 2.38 (d, J=2.5 Hz, 3H),1.45 (s, 9H); MS (ESI) m/z 437.1 (M−H), calcd for C₂₀H₂₀BrFO₃ 438.0.

To diisopropylamine (0.090 mL, 0.64 mmol, 5.0 equiv) in anhydrous THF at−78° C. was added n-BuLi (0.40 mL, 1.6 M/hexanes, 0.64 mmol, 5.0 equiv).The colorless solution was stirred at 0° C. for 10 min and cooled to−78° C. TMEDA (0.29 mL, 1.92 mmol, 15 equiv) was added, followed by thedropwise addition of compound S14-5 (0.14 g, 0.32 mmol, 2.5 equiv, in 3mL THF) over a period of 5 min. The deep red solution was stirred at−78° C. for 15 min. Enone S1-9 (62 mg, 0.13 mmol, 1.0 equiv, in 3 mLTHF) was added. The reaction was warmed from −78° C. to −10° C. withstirring over a period of 30 min, quenched by HOAc (0.12 mL) andsaturated aqueous ammonium chloride (50 mL), and extracted with EtOAc(100 mL×1, 50 mL×2). The EtOAc extracts were combined, dried over sodiumsulfate, and concentrated under reduced pressure. Reverse phase HPLCpurification yielded the desired product S14-6 as a light-yellow solid(36 mg, 34%): R_(f) 0.45 (20%. EtOAc/hexanes); ¹H NMR (400 MHz, CDCl₃) δ15.69 (br s, 1H), 7.45-7.50 (m, 2H), 7.30-7.40 (m, 3H), 5.34 (s, 2H),3.97 (br s, 1H), 3.20-3.30 (br m, 1H), 2.98-3.07 (br m, 1H), 2.1-2.7 (m,11H), 1.5-1.6 (m, 11H), 0.80 (s, 9H), 0.23 (s, 3H), 0.11 (s, 3H); MS(ESI) m/z 827.3 (M+H), calcd for C₄₀H₄₅BrFN₃O₉Si 826.2.

Compound S14-6 (36 mg, 0.044 mmol) was dissolved in acetonitrile (1.5mL). Aqueous HF (0.75 mL, 48-50%) was added. The yellow solution wasstirred at rt overnight, diluted with aqueous K₂HPO₄ (3.2 g in 16 mLwater), and extracted with dichloromethane (20 mL×3). Thedichloromethane extracts were combined, dried over sodium sulfate, andconcentrated under reduced pressure to yield crude S14-7 as abright-yellow solid (31 mg): MS (ESI) m/z 613.2 (M+H), calcd forC₂₉H₂₆BrFN₂O₇ 612.1.

The above crude product S14-7 was dissolved in MeOH (4 mL) and dioxane(2 mL). 10% Pd—C (19 mg, 0.0090 mmol, 0.2 equiv) was added. The mixturewas purged with hydrogen and stirred under 1 atm hydrogen atmosphere atrt for 1 h. The catalyst was filtered off with a small Celite pad andwashed with MeOH (5 mL×3). The yellow filtrate was concentrated underreduced pressure to yield crude S14-8 as a yellow solid (27 mg). 100% ofthe crude product was purified with reverse phase HPLC using similarconditions for S2-4-1 to yield compound S14-8 as a yellow solid (2 mg,71%, 2 steps, HCl salt): ¹H NMR (400 MHz, CD₃OD) δ 6.69 (d, J=6.1 Hz,1H), 4.06 (s, 1H), 2.80-3.50 (m, 3H), 3.03 (s, 3H), 2.95 (s, 3H),2.10-2.40 (m, 2H), 2.27 (s, 3H), 1.56-1.68 (m, 1H); MS (ESI) m/z 447.1(M+H), calcd for C₂₂H₂₃FN₂O₇ 446.2.

Compound S14-8 (90% of crude from above, 0.40 mmol) was dissolved incold sulfuric acid (2 mL, 0° C.). Nitric acid (0.12 mL, 0.5 M insulfuric acid, 0.060 mmol, 1.5 equiv) was added. The deep brown solutionwas stirred at 0° C. for 1 h. The resulting deep red solution was addeddropwise into ether (100 mL) with stirring. The yellow solid wascollected onto a small Celite pad, washed with ether (5 mL×4,discarded), and eluted with MeOH (5 mL×3). The yellow MeOH solution wascollected and concentrated under reduced pressure to yield the desiredcompound S14-9 as a yellow solid (27 mg): MS (ESI) m/z 492.3 (M+H),calcd for C₂₂H₂₂FN₃O₉ 491.1.

Compound S14-9 (25 mg, 0.036 mmol) was dissolved in MeOH (4 mL).10%/Pd—C (15 mg, 0.0070 mmol, 0.2 equiv) was added. The mixture waspurged with hydrogen and stirred at rt under 1 atm hydrogen atmospherefor 4 hrs. The catalyst was filtered off with a small Celite pad andwashed with MeOH (5 mL×3). The yellow filtrate was concentrated underreduced pressure. HPLC purification using similar conditions for S2-4-1yielded the desired product S14-10 as a deep red solid (6 mg, 31%, 3steps, bis-HCl salt): ¹H NMR (400 MHz, CD₃OD) δ 4.09 (s, 1H), 2.80-3.50(m, 3H), 3.03 (s, 3H), 2.95 (s, 3H), 2.30-2.40 (m, 1H), 2.34 (s, 3H),2.19-2.27 (m, 1H), 1.60-1.62 (m, 1H); MS (ESI) m/z 462.1 (M+H), calcdC₂₂H₂₄FN₃O₇ 461.2.

Compound S14-10 (4 mg, 0.0075 mmol, 1.0 equiv) was dissolved inacetonitrile/DMPU (0.1 mL, 1:1 v/v). t-Butylaminoacetyl chloride (2 mg,HCl salt, 0.011 mmol, 1.5 equiv, prepared by treating t-butylaminoaceticacid with excess thionyl chloride followed by concentration underreduced pressure) was added. The deep red solution was stirred at rt for3 hrs and quenched by aqueous HCl (2 mL, 0.1 N). HPLC purification usingsimilar conditions for S2-4-1 yielded the desired product S14-11 as ayellow solid (2 mg, 41%, bis-HCl salt): ¹H NMR (400 MHz, CD₃OD) δ 4.08(br s, 3H), 2.78-3.50 (m, 3H), 3.04 (s, 3H), 2.95 (s, 3H), 2.18-2.37 (m,2H), 2.21 (s, 3H), 1.60-1.62 (m, 1H), 1.42 (s, 9H); MS (ESI) m/z 575.4(M+H), calcd for C₂₈H₃₅FN₄O₈ 574.2.

Example 15 Synthesis of Compounds Via Scheme 15

The following compounds were prepared according to Scheme 15.

To an ice-cooled solution of 2-methoxy-6-methylaniline (S15-1, 25.12 g,183.10 mmol, 1 equiv) in MeOH (79 mL) and HOAc (25 mL) was added asolution of bromine (9.41 mL, 183.10 mmol) in HOAc (79 mL) dropwise viaan addition funnel. The reaction mixture was allowed to warm to rt andstirred for 2 hrs after complete addition. EtOAc (150 mL) was added, andthe solid was collected by filtration and washed with more EtOAc,yielding 37.20 g of compound S15-2 as an off-white solid (HBr salt).

4-Bromo-2-methoxy-6-methylaniline (S15-2, HBr salt, 20.00 g, 92.70 mmol,1.0 equiv) was suspended in concentrated HCl (22 mL) and crushed ice (76g) cooled in an ice-bath. A solution of NaNO₂ (6.52 g, 94.60 mmol, 1.02equiv) in H₂O (22 mL) was added dropwise. The resulting mixture wasstirred at 0° C. for 30 min and neutralized with aqueous Na₂CO₃. Asuspension of CuCN (10.4 g, 115.90 mmol, 1.25 equiv) in H₂O (44 mL) wasmixed with a solution of NaCN (14.4 g, 294.80 mmol, 3.18 equiv) in 22 mLof H₂O, and cooled in an ice-bath. The initial diazonium salt mixturewas then added to the CuCN and NaCN mixture with vigorous stirring whilemaintaining the temperature at 0° C. (toluene (180 mL) was also added inportions during the addition). The reaction mixture was stirred at 0° C.for 1 h, rt for 2 hrs, and 50° C. for another 1 h. After cooling to rt,the layers were separated. The aqueous layer was extracted with toluene.The combined organic layers were washed with brine, dried over magnesiumsulfate, and concentrated. The residue was passed through a silica gelplug, washed with toluene, and concentrated to yield 14.50 g of compoundS15-3 as a light yellow solid.

To a solution of S15-3 (11.34 g, 50.20 mmol, 1.0 equiv) in THF (100 mL)was added 1.5 M DIBAL-H in toluene (40.10 mL, 60.20 mmol, 1.2 equiv)slowly at −78° C. The reaction was allowed to warm to rt gradually andstirred overnight. After re-cooled to 0° C., the reaction was carefullyquenched by 1 N HCl. The resulting mixture was stirred at rt for 1 h andextracted three times with EtOAc. The combined EtOAc layers were washedwith H₂O, saturated aqueous NaHCO₃ and brine, dried over magnesiumsulfate, and concentrated to provide compound S15-4 as a yellow solid,which was used directly in the next step.

To a suspension of S15-4 (50.20 mmol, 1.0 equiv) in t-BuOH (200 mL) wasadded a solution of NaClO₂ (11.34 g, 100.30 mmol, 2.0 equiv) and NaH₂PO₄(34.6 g, 250.80 mmol, 5.0 equiv) in H₂O (100 mL) via an addition funnel.After complete addition, 2-methyl-2-butene (42.40 mL, 0.40 mol, 8equiv)) was added. The resulting homogenous solution was stirred at rtfor 30 min, and volatiles were removed. The residue was suspended in 150mL of H₂O. The solution was acidified to pH˜1 with 1 N HCl and extractedthree times with t-butyl methyl ether. The combined organic solution wasextracted three times with 1 N NaOH. The combined aqueous solution wasacidified with 6 N HCl, and extracted three times with EtOAc. Thecombined EtOAc extracts were washed with brine, dried over magnesiumsulfate, and concentrated to provide 8.64 g of the benzoic acidintermediate (15-4-a) as an off-white solid, which was used directly inthe next step.

To a solution of the above benzoic acid (8.64 g, 35.20 mmol, 1.0 equiv)in dichloromethane (70 mL) was added oxalyl chloride (3.76 mL, 42.30mmol, 1.2 equiv), followed by a couple of drops of DMF (caution: gasevolution). The mixture was stirred at it for 30 min and the volatileswere evaporated under reduce pressure. The residue was further driedunder high vacuum to afford the crude benzoyl chloride. The crudebenzoyl chloride was re-dissolved in dichloromethane (70 mL).Triethylamine (12.3 mL, 88.10 mmol, 2.5 equiv), phenol (3.98 g, 42.30mmol, 1.2 equiv) and DMAP (0.43 g, 3.52 mmol, 0.1 equiv) were added. Themixture was stirred at rt for 1 h. The solvent was evaporated. Theresidue was suspended in EtOAc, and the precipitate was filtered off.The organic solution was then washed with 1 N HCl (three times), H₂O,saturated aqueous NaHCO₃, and brine, dried over sodium sulfate, filteredand concentrated.

Purification of the residue by flash chromatography gave compound S15-5(10.05 g, 89%) as an off-white solid: ¹H NMR (400 MHz, CDCl₃) δ7.41-7.45 (m, 2H), 7.22-7.27 (m, 3H), 7.04 (d, J=0.9 Hz, 1H), 6.97 (d,J=0.9 Hz, 1H), 3.87 (s, 3H), 2.42 (s, 3H); MS (ESI) m/z 319.0 (M−H),calcd for C₁₅H₁₂BrO₃ 319.0.

To a solution of compound S15-5 (2.52 g, 7.87 mmol, 1.0 equiv) inacetonitrile (16 mL) was added NCS (1.10 g, 8.27 mmol, 1.05 equiv) inone portion. The resulting mixture was heated in a 60° C. oil bath for45 hrs. The solvent was evaporated. The residue was redissolved in Et₂O(400 mL), washed with 1 N NaOH, H₂O and brine, dried over sodiumsulfate, and concentrated to provide 2.76 g of compound S15-6 as a whitesolid. This material was used directly in the next step without furtherpurification:

¹H NMR (400 MHz, CDCl₃) δ 7.44 (dd, J=7.8, 7.8 Hz, 2H), 7.22-7.28 (m,3H), 7.13 (s, 1H), 3.87 (s, 3H), 2.51 (s, 3H); MS (ESI) m/z 353.0 (M−H),calcd for C₁₅H₁₁BrClO₃ 352.97.

Compound S15-6 (2.76 g, 7.76 mmol, 1.0 equiv) was dissolved in anhydrousdichloromethane (78 mL) and cooled to −78° C. A solution of borontribromide (1.0 M in dichloromethane, 7.76 mL, 7.76 mmol, 1.0 equiv) wasadded dropwise at −78° C. The resulting yellow solution was stirred at−78° C. for 15 min, and at 0° C. for 30 min. Saturated aqueous NaHCO₃was added. The mixture was stirred at rt for 10 min., and extracted withEtOAc three times. The combined organic layers were washed with brine,dried over sodium sulfate, and concentrated to provide 2.69 g of thephenol intermediate as an off-white solid. This material was useddirectly in the next step without further purification: ¹H NMR (400 MHz,CDCl₃) δ 7.46 (dd, J=7.8, 7.8 Hz, 2H), 7.32 (dd, J=7.8, 7.8 Hz, 1H),7.27 (s, 1H), 7.19 (d, J=7.8 Hz, 2H), 2.83 (s, 3H); MS (ESI) m/z 339.0(M−H), calcd for C₄H₉BrClO₃ 338.95.

The above phenol (2.65 g, 7.76 mmol, 1.0 equiv) was dissolved in acetone(40 mL), and added with K₂CO₃ (2.14 g, 15.5 mmol, 2.0 equiv) andbenzylbromide (0.97 mL, 8.15 mmol, 1.05 equiv) at rt. After stirringovernight at rt, the solution was filtered through a bed of Celite. Thesolid cake was further washed with three portions of EtOAc. The combinedorganic solution was concentrated. The residue was purified by flashchromatography to yield 2.97 g (89%) of compound S15-7 as a white solid:¹H NMR (400 MHz, CDCl₃) δ 7.33-7.43 (m, 7H), 7.19-7.26 (m, 2H), 7.05 (d,J=7.8 Hz, 2H), 5.11 (s, 2H), 2.51 (s, 3H); MS (ESI) m/z 429.0 (M−H),calcd for C₂₁H₁₅BrClO₃ 429.00.

To a solution of compound S15-7 (1.98 g, 4.59 mmol, 1.0 equiv) inanhydrous THF (23 mL) was added i-PrMgCl.LiCl (7.65 mL, 1.2 M/THF, 9.18mmol, 2.0 equiv) dropwise at −78° C. under a N₂ atmosphere. After 10min, the temperature was raised to 0° C. and the reaction was stirredfor 1 h at 0° C. DMF (1.80 mL, 22.90 mmol, 5.0 equiv) was then added.The reaction was warmed to rt, stirred for 30 min at rt, and quenched bysaturated aqueous NH₄Cl. The layers were separated and the aqueous layerwas further extracted twice with EtOAc. The combined organic layers werewashed with brine, dried over sodium sulfate, filtered, andconcentrated. Purification of the residue by flash chromatography gavecompound S15-8 (1.45 g, 83%) as a white solid: ¹H NMR (400 MHz, CDCl₃) δ10.51 (s, 1H), 7.33-7.44 (m, 8H), 7.25-7.27 (m, 1H), 7.05 (d, J=7.8 Hz,2H), 5.19 (s, 2H), 2.51 (s, 3H); MS (ESI) m/z 379.1 (M−H), calcd forC₂₂H₁₆ClO₄ 379.08.

To a solution of aldehyde S15-8 (1.66 g, 4.37 mmol, 1.0 equiv) in MeOH(22 mL) was added trimethylorthoformate (2.40 mL, 21.90 mmol, 5.0 equiv)and TsOH (83 mg, 0.44 mmol, 0.1 equiv). The reaction was heated to 65°C. for 4 hrs. The solvent was evaporated. The residue was redissolved inEtOAc (200 mL), washed with saturated aqueous NaHCO₃ and brine, driedover sodium sulfate, and concentrated. Purification of the residue byflash chromatography gave compound S15-9 (1.75 g, 94%) as a white solid:¹H NMR (400 MHz, CDCl₃) δ 7.43 (d, J=7.8 Hz, 2H), 7.34-7.37 (m, 5H),7.20-7.25 (m, 2H), 7.07 (d, J=7.8 Hz, 2H), 5.62 (s, 1H), 5.19 (s, 2H),3.36 (s, 6H), 2.48 (s, 3H); MS (ESI) m/z 425.10 (M−H), calcd forC₂₄H₂₂ClO₅ 425.12.

A solution of n-BuLi in hexanes (2.37 mL, 2.2 M, 5.23 mmol, 1.2 equiv)was added dropwise to a solution of i-Pr₂NH (0.77 mL, 5.45 mmol, 1.25equiv) in THF (27 mL) at −78° C. under a N₂ atmosphere. The resultingsolution was stirred at −78° C. for 20 min and 0° C. for 5 min, and thenre-cooled to −78° C. N,N,N′,N′-Tetramethylethylenediamine (TMEDA, 0.85mL, 5.67 mmol, 1.30 equiv) was added, followed by the dropwise additionof S15-9 (2.05 g, 4.80 mmol, 1.1 equiv) in THF (30 mL) via a cannula.After complete addition, the resulting dark-red mixture was stirred foranother hour at −78° C. and then cooled to −100° C. A solution of enone51-9 (2.10 g, 4.36 mmol, 1.0 equiv) in THF (30 mL) was added dropwisevia a cannula. The resulting red mixture was slowly warmed to −78° C.LHMDS (4.36 mL, 1.0 M/THF, 4.36 mmol, 1.0 equiv) was then added and thereaction was slowly warmed to −5° C. Saturated aqueous NH₄Cl was added.The resulting mixture was extracted three times with EtOAc. The combinedEtOAc extracts were washed with brine, dried (sodium sulfate), andconcentrated. Purification of the residue by flash chromatography gavecompound S15-10 (3.20 g, 90%) as a light yellow foam: ¹H NMR (400 MHz,CDCl₃) δ 0.16 (s, 3H), 7.22-7.52 (m, 11H), 5.55 (s, 1H), 5.38 (s, 2H),5.29 (d, J=11.4 Hz, 1H), 5.24 (d, J=11.4 Hz, 1H), 3.97 (d, J=10.4 Hz,1H), 3.46 (dd, J=4.9, 15.9 Hz, 1H), 3.38 (s, 3H), 3.29 (s, 3H),2.96-3.04 (m, 1H), 2.45-2.58 (m, 9H), 2.15 (d, J=14.6 Hz, 1H), 0.84 (s,9H), 0.28 (s, 3H); MS (ESI) m/z 815.30 (M+H), calcd for C₄₄H₅₂ClN₂O₉Si815.31.

To a solution of compound S15-10 (1.48 g, 1.82 mmol, 1.0 equiv) in THF(15 mL) was added 3 N HCl (3 mL) at 0° C. The resulting mixture wasstirred at rt for 4 hrs, diluted with EtOAc, washed with saturatedaqueous NaHCO₃ and brine, dried over sodium sulfate, and concentrated.Purification of the residue by flash chromatography gave aldehyde S15-11(1.05 g, 75%) as a light yellow foam: ¹H NMR (400 MHz, CDCl₃) δ 15.8 (s,1H), 10.5 (s, 1H), 7.28-7.50 (m, 11H), 5.36 (s, 2H), 5.28 (d, J=11.4 Hz,1H), 5.23 (d, J=11.4 Hz, 1H), 3.94 (d, J=10.4 Hz, 1H), 3.48 (dd, J=4.9,15.9 Hz, 1H), 2.96-3.06 (m, 1H), 2.44-2.60 (m, 9H), 2.16 (d, J=14.6 Hz,1H), 0.82 (s, 9H), 0.26 (s, 3H), 0.14 (s, 3H); MS (ESI) m/z 769.30(M+H), calcd for C₄₂H₄₆ClN₂O₈Si 769.26.

Compound S15-11 (30 mg, 0.039 mmol, 1.0 equiv) was dissolved in1,2-dichloroethane (1.0 mL). Isobutylamine (14 μL, 0.12 mmol, 3.0 equiv)and acetic acid (7 μL, 0.12 mmol, 3.0 equiv) were added. After stirringat rt for 1 h, sodium triacetoxyborohydride (17 mg, 0.078 mmol, 2.0equiv) was added. Stirring was continued overnight. The reaction mixturewas poured into saturated aqueous NaHCO₃ and extracted three times withdichloromethane. The combined organic extracts were washed with brine,dried over sodium sulfate, and concentrated to give the crudeintermediate, which was used directly in the next step without furtherpurification.

In a plastic vial, the above amine intermediate was dissolved in CH₃CN(1 mL). Aqueous HF (48-500%, 0.25 mL) was added. After stirring at rtfor 16 hrs, the reaction mixture was poured into aqueous solution (12.5mL) of K₂HPO₄ (1.75 g) and extracted three times with dichloromethane.The combined organic phases were washed with brine, dried, andconcentrated to yield the crude intermediate.

The above crude intermediate was dissolved in EtOAc (2.0 mL). Pd—C (10wt %, 8 mg, 300 w/w) was added. The reaction flask was briefly evacuatedand re-filled with hydrogen. The reaction mixture was stirred at rt andmonitored by LC-MS. After the reaction was complete, MeOH (5 mL) and 0.5N HCl/MeOH (0.5 mL) were added. The mixture was stirred for 30 min, andfiltered through a small pad of Celite. The filtrate was concentrated togive the crude product, which was purified by HPLC on a WatersAutopurification system using a Phenomenex Polymerx 10μ RP-γ 100 Rcolumn [30×21.20 mm, 10 micron; flow rate, 20 mL/min; Solvent A: 0.05 NHCl/water; Solvent B: MeOH; injection volume: 4.0 mL (0.05 N HCl/water);gradient: 20→100% B over 10 min; mass-directed fraction collection].Fractions containing the desired product, eluting at 7.85-8.95 min, werecollected and freeze-dried to give the desired product S15-13-1 as ayellow solid: ¹H NMR (400 MHz, CD₃OD) δ 7.16 (s, 1H), 7.16 (s, 1H), 4.38(s, 2H), 4.12 (s, 1H), 3.40 (dd, J=4.6, 16.0 Hz, 1H), 2.96-3.11 (m,10H), 2.41 (dd, J=14.0, 14.0 Hz, 1H), 2.24-2.28 (m, 1H), 2.08-2.13 (m,1H), 1.60-1.70 (m, 1H), 1.06 (d, J=6.4 Hz, 6H); MS (ESI) m/z 534.2(M+H), calcd for C₂₆H₃₃ClN₃O₇ 534.19.

The following compounds were prepared similarly to S15-13-1.

The crude product was purified by HPLC on a Waters Autopurificationsystem using a Phenomenex Polymerx 10μ RP-γ 100 R column [30×21.20 mm,10 micron; flow rate, 20 mL/min; Solvent A: 0.05 N HCl/water; Solvent B:MeOH; injection volume: 4.0 mL (0.05 N HCl/water); gradient: 20→100% Bover 10 min; mass-directed fraction collection]. Fractions containingthe desired product, eluting at 8.00-9.50 min, were collected andfreeze-dried to give the desired product S15-13-2 as a yellow solid:

¹H NMR (400 MHz, CD₃OD) δ 7.19 (s, 1H), 4.33 (s, 2H), 4.13 (s, 1H), 3.41(dd, J=4.6, 16.0 Hz, 1H), 2.96-3.10 (m, 8H), 2.40 (dd, J=15.0, 15.0 Hz,1H), 2.25-2.28 (m, 1H), 1.84 (q, J=7.3 Hz, 2H), 1.60-1.70 (m, 1H), 1.44(s, 6H), 1.04 (t, J=7.3 Hz, 3H); MS (ESI) m/z 548.3 (M+H), calcd forC₂₇H₃₅ClN₃O₇ 548.21.

The crude product was purified by HPLC on a Waters Autopurificationsystem using a Phenomenex Polymerx 10μ RP-γ 100 R column [30×21.20 mm,10 micron; flow rate, 20 mL/min; Solvent A: 0.05 N HCl/water; Solvent B:MeOH; injection volume: 4.0 mL (0.05 N HCl/water); gradient: 20→100% Bover 10 min; mass-directed fraction collection]. Fractions containingthe desired product, eluting at 8.35-9.80 min, were collected andfreeze-dried to give the desired product S15-13-3 as a yellow solid:

¹H NMR (400 MHz, CD₃OD) δ 7.19 (s, 1H), 4.44 (s, 2H), 4.13 (s, 1H), 3.41(dd, J=4.6, 16.0 Hz, 1H), 2.96-3.10 (m, 8H), 2.41 (dd, J=15.0, 15.0 Hz,1H), 2.23-2.28 (m, 1H), 1.60-1.70 (m, 1H), 1.34 (s, 6H), 1.21-1.26 (m,1H), 0.69-0.72 (m, 2H), 0.60-0.63 (m, 2H); MS (ESI) m/z 560.3 (M+H),calcd for C₂₈H₃₅ClN₃O₇ 560.21.

The crude product was purified by HPLC on a Waters Autopurificationsystem using a Phenomenex Polymerx 10μ RP-γ 100 R column [30×21.20 mm,10 micron; flow rate, 20 mL/min; Solvent A: 0.05 N HCl/water; Solvent B:MeOH; injection volume: 4.0 mL (0.05 N HCl/water); gradient: 20→100% Bover 10 min; mass-directed fraction collection]. Fractions containingthe desired product, eluting at 7.15-8.50 min, were collected andfreeze-dried to give the desired product S15-13-4 as a yellow solid:

¹H NMR (400 MHz, CD₃OD) δ 7.21 (s, 1H), 4.72 (t, J=13.2 Hz, 1H),4.10-4.15 (m, 2H), 3.38-3.55 (m, 2H), 2.95-3.10 (m, 8H), 2.41 (dd,J=15.0, 15.0 Hz, 1H), 1.96-2.28 (m, 5H), 1.96-2.28 (m, 5H), 1.66 (s,3H), 1.63-1.66 (m, 1H), 1.45 (s, 3H); MS (ESI) m/z 560.3 (M+H), calcdfor C₂₈H₃₅ClN₃O₇ 560.21.

The crude product was purified by HPLC on a Waters Autopurificationsystem using a Phenomenex Polymerx 10μ RP-γ 100 R column [30×21.20 mm,10 micron; flow rate, 20 mL/min; Solvent A: 0.05 N HCl/water; Solvent B:MeOH; injection volume: 4.0 mL (0.05 N HCl/water); gradient: 20→100% Bover 10 min; mass-directed fraction collection]. Fractions containingthe desired product, eluting at 7.65-8.50 min, were collected andfreeze-dried to give the desired product S15-13-5 as a yellow solid:

¹H NMR (400 MHz, CD₃OD) δ 7.20 (s, 1H), 4.24 (s, 2H), 4.13 (s, 1H), 3.41(dd, J=4.6, 16.0 Hz, 1H), 2.94-3.14 (m, 10H), 2.41 (dd, J=15.0, 15.0 Hz,1H), 2.24-2.30 (m, 1H), 1.60-1.70 (m, 1H), 1.08 (s, 9H); MS (ESI) m/z548.3 (M+H), calcd for C₂₇H₃₅ClN₃O₇ 548.21.

The crude product was purified by HPLC on a Waters Autopurificationsystem using a Phenomenex Polymerx 10μ RP-γ 100 R column [30×21.20 mm,10 micron; flow rate, 20 mL/min; Solvent A: 0.05 N HCl/water; Solvent B:MeOH; injection volume: 4.0 mL (0.05 N HCl/water); gradient: 0→100% Bover 20 min; mass-directed fraction collection]. Fractions containingthe desired product, eluting at 13.80-14.90 min, were collected andfreeze-dried to give the desired product S15-13-6 as a yellow solid: ¹HNMR (400 MHz, CD₃OD) δ 7.14 (s, 1H), 4.40 (s, 2H), 4.13 (s, 1H), 3.40(dd, J=4.6, 16.0 Hz, 1H), 2.94-3.14 (m, 10H), 2.40 (dd, J=15.0, 15.0 Hz,1H), 2.25-2.28 (m, 1H), 1.60-1.70 (m, 1H), 1.16-1.21 (m, 1H), 0.72-0.77(m, 2H), 0.43-0.47 (m, 2H); MS (ESI) m/z 532.2 (M+H), calcd forC₂₆H₃₁ClN₃O₇ 532.18.

The crude product was purified by HPLC on a Waters Autopurificationsystem using a Phenomenex Polymerx 10μ RP-γ 100 R column [30×21.20 mm,10 micron; flow rate, 20 mL/min; Solvent A: 0.05 N HCl/water; Solvent B:MeOH; injection volume: 4.0 mL (0.05 N HCl/water); gradient: 0→100% Bover 20 min; mass-directed fraction collection]. Fractions containingthe desired product, eluting at 15.55-16.00 min, were collected andfreeze-dried to give the desired product S15-13-7 as a yellow solid: ¹HNMR (400 MHz, CD₃OD) δ 7.15 (s, 1H), 4.37 (s, 2H), 4.12 (s, 1H), 3.40(dd, J=4.6, 16.0 Hz, 1H), 2.94-3.14 (m, 10H), 2.40 (dd, J=15.0, 15.0 Hz,1H), 2.24-2.28 (m, 1H), 1.60-1.88 (m, 7H), 1.21-1.35 (m, 3H), 1.01-1.09(m, 2H); MS (ESI) m/z 574.3 (M+H), calcd for C₂₉H₃₇ClN₃O₇ 574.22.

The crude product was purified by HPLC on a Waters Autopurificationsystem using a Phenomenex Polymerx 10μ RP-γ 100 R column [30×21.20 mm,10 micron; flow rate, 20 mL/min; Solvent A: 0.05 N HCl/water; Solvent B:MeOH; injection volume: 4.0 mL (0.05 N HCl/water); gradient: 0-100% Bover 20 min; mass-directed fraction collection]. Fractions containingthe desired product, eluting at 13.85-14.90 min, were collected andfreeze-dried to give the desired product S15-13-8 as a yellow solid: ¹HNMR (400 MHz, CD₃OD) δ 7.18 (s, 1H), 4.40 (s, 2H), 4.13 (s, 1H), 3.41(dd, J=4.6, 16.0 Hz, 1H), 3.32-3.36 (m, 1H), 2.94-3.11 (m, 8H), 2.40(dd, J=15.0, 15.0 Hz, 1H), 2.20-2.28 (m, 2H), 1.60-1.70 (m, 1H), 1.34(d, J=6.8 Hz, 3H), 1.06 (d, J=6.8 Hz, 3H), 1.01 (d, J=6.8 Hz, 3H); MS(ESI) m/z 548.2 (M+H), calcd for C₂₇H₃₅ClN₃O₇ 548.21.

The crude product was purified by HPLC on a Waters Autopurificationsystem using a Phenomenex Polymerx 10μ RP-γ 100 R column [30×21.20 mm,10 micron; flow rate, 20 mL/min; Solvent A: 0.05 N HCl/water; Solvent B:MeOH; injection volume: 4.0 mL (0.05 N HCl/water); gradient: 20→100% Bover 10 min; mass-directed fraction collection]. Fractions containingthe desired product, eluting at 9.60-10.85 min, were collected andfreeze-dried to give the desired product S15-13-9 as a yellow solid:

¹H NMR (400 MHz, CD₃OD) δ 7.20 (s, 1H), 4.41 (s, 2H), 4.15 (s, 1H), 3.40(dd, J=4.6, 16.0 Hz, 1H), 2.83-3.15 (m, 10H), 2.39 (dd, J=15.0, 15.0 Hz,1H), 2.26-2.32 (m, 1H), 2.03 (br. s, 3H), 1.59-1.81 (m, 13H); MS (ESI)m/z 626.3 (M+H), calcd for C₃₃H₄₁ClN₃O₇ 626.26.

The crude product was purified by HPLC on a Waters Autopurificationsystem using a Phenomenex Polymerx 10μ RP-γ 100 R column [30×21.20 mm,10 micron; flow rate, 20 mL/min; Solvent A: 0.05 N HCl/water; Solvent B:MeOH; injection volume: 4.0 mL (0.05 N HCl/water); gradient: 10→100% Bover 20 min; mass-directed fraction collection]. Fractions containingthe desired product, eluting at 15.15-16.45 min, were collected andfreeze-dried to give the desired product S15-13-10 as a yellow solid: ¹HNMR (400 MHz, CD₃OD) δ 7.17 (s, 1H), 4.34 (s, 2H), 4.13 (s, 1H), 3.41(dd, J=4.6, 16.0 Hz, 1H), 2.94-3.15 (m, 8H), 2.40 (dd, J=15.0, 15.0 Hz,1H), 2.24-2.28 (m, 1H), 1.83 (s, 2H), 1.60-1.70 (m, 1H), 1.58 (s, 6H),1.11 (s, 9H); MS (ESI) m/z 590.3 (M+H), calcd for C₃₀H₄₁ClN₃O₇ 590.26.

To a solution of compound S15-13-5 (12 mg, 0.022 mmol, 1.0 equiv) in DMF(0.5 mL) was added sequentially triethylamine (6 μL, 0.045 mmol, 2.0equiv), HCHO (37 wt % in H₂O, 5 μL, 0.067 mmol, 3.0 equiv) and InCl₃(0.5 mg, 0.0022 mmol, 0.1 equiv) at rt. After stirring for 5 min,Na(OAc)₃BH (10 mg, 0.045 mmol, 2.0 equiv) was added. Stirring wascontinued for another hour. HCl/MeOH (0.20 mL, 0.5 N) was added. Theresulting mixture was added dropwise to vigorously stirring diethylether (100 mL). The precipitate was collected onto a small Celite padand washed three times with more diethyl ether. The Celite pad was theneluted several times with MeOH. The MeOH solution was collected andconcentrated to provide the crude product, which was purified by HPLC ona Waters Autopurification system using a Phenomenex Polymerx 10μ RP-γ100 R column [30×21.20 mm, 10 micron; flow rate, 20 mL/min; Solvent A:0.05 N HCl/water; Solvent B: MeOH; injection volume: 4.0 mL (0.05 NHCl/water); gradient: 0→100% B over 20 min; mass-directed fractioncollection]. Fractions containing the desired product, eluting at13.90-15.40 min, were collected and freeze-dried to give the desiredproduct S15-13-11 as a yellow solid: ¹H NMR (400 MHz, CD₃OD) δ 7.28 (s,1H), 4.71-4.78 (m, 1H), 4.43-4.48 (m, 1H), 4.13 (s, 1H), 3.41 (dd,J=4.6, 16.0 Hz, 1H), 2.94-3.15 (m, 13H), 2.44 (dd, J=15.0, 15.0 Hz, 1H),2.24-2.28 (m, 1H), 1.60-1.70 (m, 1H), 1.09 (s, 9H); MS (ESI) m/z 562.2(M+H), calcd for C₂₈H₃₇ClN₃O₇ 562.22.

Compound S15-13-12 was prepared similarly from 515-13-8. The crudeproduct was purified by HPLC on a Waters Autopurification system using aPhenomenex Polymerx 10 g RP-γ 100 R column [30×21.20 mm, 10 micron; flowrate, 20 mL/min; Solvent A: 0.05 N HCl/water; Solvent B: MeOH; injectionvolume: 4.0 mL (0.05 N HCl/water); gradient: 0-*100% B over 20 min;mass-directed fraction collection]. Fractions containing the desiredproduct, eluting at 14.15-15.25 min, were collected and freeze-dried togive the desired product S15-13-12 as a yellow solid: ¹H NMR (400 MHz,CD₃OD) δ 7.22 (s, 1H), 4.26-4.76 (m, 2H), 4.12 (s, 1H), 3.34-3.44 (m,2H), 2.82-3.11 (m, 11H), 2.18-2.47 (m, 3H), 1.60-1.70 (m, 1H), 1.39-1.46(m, 3H), 1.03-1.08 (m, 6H); MS (ESI) m/z 562.2 (M+H), calcd forC₂₈H₃₇ClN₃O₇ 562.22.

Compound S15-13-13 was prepared similarly from S15-13-9. The crudeproduct was purified by HPLC on a Waters Autopurification system using aPhenomenex Polymerx 10μ RP-γ 100 R column [30×21.20 mm, 10 micron; flowrate, 20 mL/min; Solvent A: 0.05 N HCl/water; Solvent B: MeOH; injectionvolume: 4.0 mL (0.05 N HCl/water); gradient: 20-100% B over 20 min;mass-directed fraction collection]. Fractions containing the desiredproduct, eluting at 17.00-18.85 min, were collected and freeze-dried togive the desired product S15-13-13 as a yellow solid: ¹H NMR (400 MHz,CD₃OD) δ 7.26 (s, 1H), 4.68-4.74 (m, 1H), 4.43-4.47 (m, 1H), 4.12 (s,1H), 3.42 (dd, J=4.6, 16.0 Hz, 1H), 2.94-3.12 (m, 13H), 2.45 (dd,J=15.0, 15.0 Hz, 1H), 2.24-2.29 (m, 1H), 2.02 (br. s, 3H), 1.57-1.81 (m,13H); MS (ESI) m/z 640.2 (M+H), calcd for C₃₄H₄₃ClN₃O₇ 640.27.

Compound S15-13-14 was prepared similarly from S15-13-10. The crudeproduct was purified by HPLC on a Waters Autopurification system using aPhenomenex Polymerx 10μ RP-γ 100 R column [30×21.20 mm, 10 micron; flowrate, 20 mL/min; Solvent A: 0.05 N HCl/water; Solvent B: MeOH; injectionvolume: 4.0 mL (0.05 N HCl/water); gradient: 10-100% B over 20 min;mass-directed fraction collection]. Fractions containing the desiredproduct, eluting at 16.35-17.65 min, were collected and freeze-dried togive the desired product S15-13-14 as a yellow solid: ¹H NMR (400 MHz,CD₃OD) δ 7.17 (s, 1H), 4.12-4.18 (m, 1H), 4.11 (s, 1H), 3.40-3.50 (m,2H), 2.94-3.15 (m, 8H), 2.75 (s, 3H), 2.39-2.48 (m, 1H), 2.24-2.28 (m,1H), 1.83-2.00 (m, 2H), 1.73 (s, 3H), 1.60-1.70 (m, 1H), 1.63 (s, 3H),1.14 (s, 9H); MS (ESI) m/z 604.3 (M+H), calcd for C₃₁H₄₃ClN₃O₇ 604.27.

To a solution of compound S15-8 (0.39 g, 1.02 mmol, 1.0 equiv) in1,2-dichloroethane (10 mL) was added t-butylamine (0.13 mL, 1.22 mmol,1.2 equiv) and acetic acid (0.18 mL, 3.05 mmol, 3.0 equiv). Afterstirring at rt for 2.5 hrs, sodium triacetoxyborohydride (0.43 g, 2.03mmol, 2.0 equiv) was added. Stirring was continued overnight. Thereaction mixture was poured into saturated aqueous NaHCO₃ and extractedthree times with dichloromethane. The combined organic extracts werewashed with brine, dried over sodium sulfate, and concentrated to givethe crude intermediate as an off-white oil. The crude intermediate wasredissolved in 1,2-dichloroethane (10 mL). Formaldehyde (37 wt % in H₂O,0.76 mL, 10.20 mmol, 10 equiv) and acetic acid (0.18 mL, 3.05 mmol, 3.0equiv) were added After stirring at rt for 1 h, sodiumtriacetoxyborohydride (0.43 g, 2.03 mmol, 2.0 equiv) was added. Stirringwas continued for another hour. The reaction mixture was poured intosaturated aqueous NaHCO₃ and extracted three times with dichloromethane.The combined organic extracts were washed with brine, dried over sodiumsulfate, and concentrated. Purification of the residue by flashchromatography gave compound S15-15-1 (0.35 g) as a white solid: ¹H NMR(400 MHz, CDCl₃) δ 7.43 (d, J=7.8 Hz, 2H), 7.20-7.40 (m, 7H), 7.12 (d,J=7.8 Hz, 2H), 5.18 (s, 2H), 3.59 (s, 2H), 2.44 (s, 3H), 2.09 (s, 3H),1.10 (s, 9H); MS (ESI) m/z 452.3 (M+H), calcd for C₂₇H₃₁ClNO₃ 452.19.

Compound S15-12-1 was prepared by the procedure of S15-10 employingcompound S15-15-1: ¹H NMR (400 MHz, CDCl₃) δ 16.0 (s, 1H), 7.22-7.52 (m,11H), 5.36 (s, 2H), 5.27 (s, 2H), 3.97 (d, J=10.4 Hz, 1H), 3.55 (s, 2H),3.42 (dd, J=4.9, 15.9 Hz, 1H), 2.93-3.04 (m, 1H), 2.43-2.53 (m, 9H),2.13 (d, J=14.6 Hz, 1H), 2.01 (s, 3H), 1.07 (s, 9H), 0.84 (s, 9H), 0.28(s, 3H), 0.13 (s, 3H); MS (ESI) m/z 840.4 (M+H), calcd forC₄₇H₅₉ClN₃O₇Si 840.37.

In a plastic vial, compound S15-12-1 (85 mg, 0.10 mmol) was dissolved inCH₃CN (2 mL). Aqueous HF (48-50%, 0.5 mL) was added. After stirring atrt for 7 hrs, the reaction mixture was poured into an aqueous solution(25 mL) of K₂HPO₄ (3.5 g). The resulting mixture was extracted threetimes with dichloromethane. The combined organic phases were washed withbrine, dried, and concentrated under reduced pressure to yield the crudedesilylated product.

The above crude intermediate was dissolved in EtOAc (6 mL). Pd—C (10 wt%, 22 mg) was added. The reaction flask was briefly evacuated andre-filled with hydrogen. The reaction mixture was stirred at rt andmonitored by LC-MS. After the reaction was complete, MeOH (5 mL) and 0.5N HCl/MeOH (0.5 mL) were added. The mixture was stirred for 30 min andfiltered through a small pad of Celite. The filtrate was concentrated togive the crude product, which was purified by HPLC on a WatersAutopurification system using a Phenomenex Polymerx 10μ RP-γ 100 Rcolumn [30×21.20 mm, 10 micron; flow rate, 20 mL/min; Solvent A: 0.05 NHCl/water; Solvent B: MeOH; injection volume: 4.0 mL (0.05 N HCl/water);gradient: 20→100%/B over 10 min: mass-directed fraction collection].Fractions containing the desired product, eluting at 6.30-8.85 min, werecollected and freeze-dried to give the desired product S15-13-15 as ayellow solid: ¹H NMR (400 MHz, CD₃OD) δ 7.20 (s, 1H), 4.80-4.87 (m, 1H),4.12-4.20 (m, 1H), 4.12 (s, 1H), 3.38-3.40 (m, 1H), 2.96-3.11 (m, 8H),2.75 (s, 3H), 2.38-2.40 (m, 1H), 2.24-2.28 (m, 1H), 1.60-1.70 (m, 1H),1.57 (s, 9H); MS (ESI) m/z 548.2 (M+H), calcd for C₂₇H₃₅ClN₃O₇ 548.21.

Alternatively, the crude desilylated product of S15-12-1 (13 mg) wasdissolved in 0.5 N HCl/MeOH (0.07 mL). The volatiles were evaporated.The residue was redissolved in MeOH (2 mL) and added with Pd—C (10 wt %,7 mg). The reaction flask was briefly evacuated and re-filled withhydrogen. The reaction mixture was stirred at rt and monitored by LC-MS.After all the reaction was complete, the reaction mixture was filteredthrough a small pad of Celite. The filtrate was concentrated to yieldthe crude product, which was purified by HPLC on a WatersAutopurification system using a Phenomenex Polymerx 10μ RP-γ 100 Rcolumn [30×21.20 mm, 10 micron; flow rate, 20 mL/min; Solvent A: 0.05 NHCl/water; Solvent B: CH₃CN; injection volume: 4.0 mL (0.05 NHCl/water); gradient: 10-150% B over 15 min; mass-directed fractioncollection]. Fractions containing the desired product, eluting at6.08-8.75 min, were collected and freeze-dried to give the following twoproducts.

S15-14-1, a yellow solid: ¹H NMR (400 MHz, CD₃OD) δ 7.01 (s, 1H), 6.93(s, 1H), 4.65 (d, J=12.8 Hz, 1H), 4.08 (s, 1H), 3.90 (d, J=12.8 Hz, 1H),2.96-3.11 (m, 9H), 2.70 (s, 3H), 2.58-2.68 (m, 1H), 2.19-2.22 (m, 1H),1.60-1.70 (m, 1H), 1.53 (s, 9H); MS (ESI) m/z 514.3 (M+H), calcd forC₂₇H₃₆N₃O₇ 514.25.

S15-14-2, a yellow solid: ¹H NMR (400 MHz, CD₃OD) δ 6.62 (s, 1H), 6.59(s, 1H), 4.06 (s, 1H), 2.77-3.11 (m, 9H), 2.51 (dd, J=14.2, 14.2 Hz,1H), 2.30 (s, 3H), 2.14-2.17 (m, 1H), 1.52-1.62 (m, 1H); MS (ESI) m/z429.3 (M+H), calcd for C₂₂H₂₅N₂O₇ 429.16.

The following compounds were prepared using similar procedures to thatof S15-13-1, S15-13-11, S15-13-15 or S15-14-1.

S15-13-16, a yellow solid: ¹H NMR (400 MHz, CD₃OD) δ 7.26 (s, 1H), 4.53(s, 2H), 4.13 (s, 1H), 3.30-3.45 (m, 5H), 2.96-3.15 (m, 8H), 2.40 (dd,J=15.9, 15.9 Hz, 1H), 2.25-2.29 (m, 1H), 1.61-1.79 (m, 5H), 1.09 (s,3H), 1.03 (s, 3H); MS (ESI) m/z 574.3 (M+H), calcd for C₂₉H₃₇ClN₃O₇574.22.

S15-14-3, a yellow solid: ¹H NMR (400 MHz, CD₃OD) δ 7.00 (s, 1H), 6.95(s, 1H), 4.28 (s, 2H), 4.09 (s, 1H), 2.96-3.15 (m, 13H), 2.61 (dd,J=15.9, 15.9 Hz, 1H), 2.18-2.22 (m, 1H), 1.59-1.75 (m, 5H), 1.09 (s,3H), 1.04 (s, 3H); MS (ESI) m/z 540.3 (M+H), calcd for C₂₉H₃₈N₃O₇540.26.

S15-14-4, a yellow solid: ¹H NMR (400 MHz, CD₃OD) δ 6.97 (s, 1H), 6.90(s, 1H), 4.18 (s, 2H), 4.09 (s, 1H), 2.94-3.14 (m, 11H), 2.60 (dd,J=15.0, 15.0 Hz, 1H), 2.19-2.22 (m, 1H), 1.59-1.65 (m, 1H), 1.10-1.15(m, 1H), 0.71-0.74 (m, 2H), 0.40-0.43 (m, 2H); MS (ESI) m/z 497.2 (M+H),calcd for C₂₆H₃₂N₃O₇ 497.22.

¹H NMR (400 MHz, CD₃OD) δ 7.31 (s, 1H), 4.56 (dd, J=19.2 Hz, 13.6 Hz,2H), 4.15 (s, 1H), 4.08-3.98 (m, 2H), 3.90-3.79 (m, 2H), 3.53-3.33 (m,5H), 3.20-2.90 (m, 8H), 2.45-2.36 (m, 1H), 2.32-2.25 (m, 1H), 1.71-160(m, 1H); MS (ESI) m/z 548.1 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.16 (s, 1H), 4.40 (s, 2H), 4.14 (s, 1H),3.50-3.36 (m, 1H), 3.32-3.21 (m, 1H), 3.18-2.90 (m, 8H), 2.48-2.36 (m,1H), 2.31-2.20 (m, 3H), 1.98-1.88 (m, 2H), 1.80-1.60 (m, 2H), 1.50-1.35(m, 4H), 1.34-1.20 (m, 1H); MS (ESI) m/z 560.1 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.13 (s, 1H), 4.26 (s, 2H), 4.13 (s, 1H),3.95-3.86 (m, 1H), 3.45-3.37 (m, 1H), 3.18-2.95 (m, 8H), 2.45-2.33 (m,3H), 2.32-2.20 (m, 3H), 2.02-1.90 (m, 2H), 1.72-1.60 (m, 1H); MS (ESI)m/z 532.1 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.16 (s, 1H), 4.38 (s, 2H), 4.13 (s, 1H),3.79-3.65 (m, 1H), 3.45-3.38 (m, 1H), 3.17-2.95 (m, 8H), 2.48-2.38 (m,1H), 2.30-2.15 (m, 3H), 1.91-1.78 (m, 2H), 1.80-1.67 (m, 5H); MS (ESI)m/z 546.1 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.24 (s, 1H), 4.72-4.56 (m, 2H), 4.50-4.32 (m,1H), 4.14 (s, 1H), 3.97-3.78 (m, 1H), 3.75-3.50 (m, 2H), 3.46-3.38 (m,1H), 3.20-2.90 (m, 9H), 2.70-2.52 (m, 1H), 2.50-2.38 (m, 1H), 2.32-2.24(m, 1H), 2.20-2.05 (m, 1H), 1.97 (s, 3H), 1.73-1.61 (m, 1H); MS (ESI)m/z 589.0 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.24 (s, 1H), 4.72-4.56 (m, 2H), 4.48-4.33 (m,1H), 4.14 (s, 1H), 3.98-3.79 (m, 1H), 3.75-3.50 (m, 2H), 3.45-3.38 (m,1H), 3.18-2.90 (m, 9H), 2.70-2.51 (m, 1H), 2.50-2.38 (m, 1H), 2.32-2.24(m, 1H), 2.20-2.05 (m, 1H), 1.97 (s, 3H), 1.73-1.61 (m, 1H); MS (ESI)m/z 589.0 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.20 (s, 1H), 4.42-4.32 (m, 2H), 4.16 (s, 1H),3.71-3.60 (m, 1H), 3.46-3.41 (m, 1H), 3.20-2.95 (m, 8H), 2.71 (br s,1H), 2.46-2.25 (m, 4H), 2.20-2.18 (m, 1H), 1.75-1.52 (m, 4H), 1.60-1.50(m, 2H), 1.50-1.41 (m, 1H), 1.24-1.16 (m, 1H); MS (ESI) m/z 572.2 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.19 (s, 1H), 4.64 (s, 2H), 4.14 (s, 1H),3.48-3.39 (m, 1H), 3.10-2.95 (m, 8H), 2.48-2.38 (m, 1H), 2.32-2.25 (m,1H), 1.68-1.59 (m, 1H), 1.50-1.39 (m, 1H), 1.05-0.97 (m, 2H), 0.88-0.82(m, 2H), 0.78-0.73 (m, 2H), 0.45-0.38 (m, 2H); MS (ESI) m/z 558.1 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.27 (s, 1H), 4.51 (s, 2H), 4.15 (s, 1H),3.62-3.53 (m, 2H), 3.47-3.38 (m, 1H), 3.24-2.90 (m, 10H), 2.49-2.37 (m,1H), 2.32-2.25 (m, 1H), 2.02-1.93 (m, 2H), 1.70-1.58 (m, 2H), 1.57-1.24(m, 6H), 1.00-0.89 (m, 3H); MS (ESI) m/z 588.2 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.25 (s, 1H), 4.49 (s, 2H), 4.13 (s, 1H),3.65-3.58 (m, 2H), 3.49-3.38 (m, 1H), 3.20-2.95 (m, 10H), 2.49-2.38 (m,1H), 2.31-2.24 (m, 1H), 2.02-1.93 (m, 2H), 1.71-1.55 (m, 3H), 1.48-1.38(m, 1H), 0.91 (s, 9H); MS (ESI) m/z 602.2 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.27 (s, 1H), 4.51 (s, 2H), 4.15 (s, 1H),3.65-3.56 (m, 2H), 3.48-3.38 (m, 1H), 3.23-2.95 (m, 10H), 2.48-3.38 (m,1H), 2.32-2.26 (m, 1H), 2.02-1.93 (m, 2H), 1.72-1.38 (m, 5H), 0.95 (d,J=6.4 Hz, 6H); MS (ESI) m/z 588.3 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.47-7.20 (m, 6H), 4.58 (s, 2H), 4.14 (s, 1H),3.75-3.65 (m, 1H), 3.57-3.35 (m, 2H), 3.20-2.85 (m, 9H), 2.61-2.40 (m,2H), 2.31-2.19 (m, 1H), 2.18-2.00 (m, 4H), 1.73-1.60 (m, 1H); MS (ESI)m/z 622.0 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.26 (s, 1H), 4.51 (s, 2H), 4.14 (s, 1H),3.64-3.57 (m, 2H), 3.46-3.37 (m, 1H), 3.32 (s, 3H), 3.30-2.25 (m, 2H),3.25-2.95 (m, 10H), 2.48-2.38 (m, 1H), 2.31-2.24 (m, 1H), 2.02-1.98 (m,3H), 1.71-1.52 (m, 3H); MS (ESI) m/z 590.0 (M+H).

MS (ESI) m/z 588.1.4 (M+H), calcd for C₃₀H₃₉ClN₃O₉ 588.24.

¹H NMR (400 MHz, CD₃OD) δ 7.30 (s, 1H), 4.53 (dd, J=18.4 Hz, 13.6 Hz,2H), 4.15 (s, 1H), 3.48-3.38 (m, 3H), 3.20-2.95 (m, 8H), 2.80-2.70 (m,2H), 2.48-2.38 (m, 1H), 2.34-2.26 (m, 1H), 2.10-1.95 (m, 2H), 1.91-1.82(m, 1H), 1.72-1.61 (m, 1H), 1.00 (d, J=6.4 Hz, 6H); MS (ESI) m/z 574.5(M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.32 (s, 1H), 4.60-4.32 (m, 2H), 4.15 (s, 1H),3.50-3.38 (m, 2H), 3.20-2.94 (m, 9H), 2.83-2.70 (m, 1H), 2.48-2.38 (m,1H), 2.35-2.10 (m, 3H), 2.08-1.95 (m, 1H), 1.72-1.53 (m, 2H), 1.50-1.40(m, 1H), 1.19 (d, J=6.8 Hz, 3H), 0.99 (d, J=6.8 Hz, 3H); MS (ESI) m/z574.3 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.22 (s, 1H), 4.56-4.48 (m, 2H), 4.13 (s, 1H),2.43-3.39 (m, 1H), 3.20-2.95 (m, 12H), 2.45-2.38 (m, 1H), 2.29-2.26 (m,1H), 1.80-1.59 (m, 8H), 1.42-1.12 (m, 7H), 1.08-0.93 (m, 2H); MS (ESI)m/z 616.1 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.06 (s, 1H), 4.30 (s, 2H), 4.02 (s, 1H),3.35-3.28 (m, 1H), 3.08-2.85 (m, 10H), 2.38-2.28 (m, 1H), 2.21-2.10 (m,2H), 1.90-1.78 (m, 2H), 1.68-1.49 (m, 5H), 1.28-1.12 (m, 2H); MS (ESI)m/z 560.3 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.17 (s, 1H), 4.38 (s, 2H), 4.13 (s, 1H),3.44-3.30 (m, 2H), 3.18-2.88 (m, 8H), 2.45-2.35 (m, 1H), 2.31-2.24 (m,1H), 2.03-1.90 (m, 1H), 1.70-1.58 (m, 2H), 1.43 (d, J=7.0 Hz, 3H), 1.05(t, J=7.2 Hz, 3H); MS (ESI) m/z 534.0 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.16 (s, 1H), 4.40 (s, 2H), 4.11 (s, 1H),3.92-3.86 (m, 2H), 3.80-3.70 (m, 1H), 3.57-3.54 (m, 1H), 3.42-3.34 (m,1H), 3.22-3.19 (m, 1H), 3.15-2.85 (m, 8H), 2.72-2.60 (m, 1H), 2.43-2.35(m, 1H), 2.28-2.13 (m, 2H), 1.76-1.58 (m, 2H); MS (ESI) m/z 562.1 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.20 (s, 1H), 4.57 (s, 2H), 4.10 (s, 1H), 3.97(dd, J=12.0 Hz and 8.0 Hz, 1H), 3.86 (dd, J=12.0 Hz and 7.6 Hz, 1H),3.41 (dd, J=16.4 Hz and 4.8 Hz, 1H), 3.13-2.94 (m, 9H), 2.44-2.37 (m,1H), 2.28-2.20 (m, 1H), 1.69-1.59 (m, 1H), 1.08 (s, 9H); MS (ESI) m/z578.1 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.21 (s, 1H), 4.44 (s, 2H), 4.14 (s, 1H), 3.42(dd, J=12.0 Hz and 4.8 Hz, 1H), 3.22-2.87 (m, 10H), 2.48-2.38 (m, 1H),2.31-2.25 (m, 1H), 2.00-1.80 (m, 6H), 1.70-1.58 (m, 3H), 0.89 (t, J=7.6Hz, 3H); MS (ESI) m/z 574.2 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.75-7.65 (m, 2H), 7.60-7.48 (m, 3H), 6.97 (s,1H), 4.12 (s, 1H), 4.00 (s, 2H), 3.37-3.32 (m, 1H), 3.10-2.95 (m, 8H),2.41-2.32 (m, 1H), 2.30-2.20 (m, 1H), 1.89 (s, 6H), 1.70-1.59 (m, 1H);MS (ESI) m/z 596.3 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.15 (s, 1H), 4.38 (s, 2H), 4.14 (s, 1H), 3.42(dd, J=16.0 Hz and 4.4 Hz, 1H), 3.23-2.96 (m, 10H), 2.47-2.38 (m, 1H),2.32-2.25 (m, 1H), 1.81-1.60 (m, 8H), 1.45-1.17 (m, 4H), 1.08-0.96 (m,2H); MS (ESI) m/z 588.2 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.25 (s, 1H), 4.50 (s, 2H), 4.14 (s, 1H),3.90-3.65 (m, 6H), 3.43 (dd, J=16.0 Hz and 4.4 Hz, 1H), 3.20-2.90 (m,10H), 2.46-2.35 (m, 1H), 2.31-2.22 (m, 1H), 2.20-2.00 (m, 4H), 1.71-1.60(m, 1H); MS (ESI) m/z 575.3 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.17 (s, 1H), 4.35 (s, 2H), 4.11 (s, 1H), 3.41(dd, J=16.0 Hz and 4.4 Hz, 1H), 3.15-2.95 (m, 8H), 2.46-2.38 (m, 1H),2.28-2.22 (m, 1H), 2.00-1.93 (m, 2H), 1.83-1.62 (m, 6H), 1.61-1.49 (m,6H); MS (ESI) m/z 574.0 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.16 (s, 1H), 4.22 (s, 2H), 4.14 (s, 1H), 3.41(dd, J=16.4 Hz and 4.4 Hz, 1H), 3.18-2.32 (m, 8H), 2.55-2.35 (m, 3H),2.31-2.22 (m, 1H), 2.18-2.08 (m, 2H), 2.05-1.93 (m, 2H), 1.66 (s, 3H);MS (ESI) m/z 546.0 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.27 (s, 1H), 4.55-4.47 (m, 2H), 4.13 (s, 1H),3.86 (m, 1H), 3.61-3.52 (m, 1H), 3.50-3.35 (m, 3H), 3.30-2.94 (m, 9H),2.45-2.35 (m, 1H), 2.31-2.22 (m, 1H), 2.18-1.98 (m, 2H), 1.95-1.87 (m,1H), 1.85-1.70 (m, 1H), 1.70-1.56 (m, 1H); MS (ESI) m/z 562.1 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.32-7.23 (m, 5H), 2.48-2.38 (m, 2H), 4.13 (s,1H), 3.65-3.38 (m, 6H), 3.20-2.95 (m, 8H), 2.84 (s, 3H), 2.50-2.38 (m,1H), 2.32-2.25 (m, 1H), 1.72-1.60 (m, 1H); MS (ESI) m/z 608.0 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.20-7.35 (m, 5H), 4.65-4.40 (m, 3H), 4.14 (s,1H), 3.60-3.38 (m, 6H), 3.20-2.95 (m, 9H), 2.50-2.39 (m, 1H), 2.33-2.26(m, 1H), 1.73-1.61 (m, 1H), 1.43 (t, J=7.6 Hz, 3H); MS (ESI) m/z 622.1(M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.25 (s, 1H), 4.74 (t, J=13.6 Hz, 1H), 4.32(t, J=11.6 Hz, 1H), 4.16 (s, 1H), 3.43 (dd, J=16.0 Hz and 3.6 Hz, 1H),3.26-2.85 (m, 13H), 2.47-2.40 (m, 1H), 2.32-2.90 (m, 1H), 2.20-2.08 (m,1H), 1.95-1.50 (m, 11H), 1.40-1.25 (m, 2H); MS (ESI) m/z 602.0 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.26 (s, 1H), 4.64 (t, J=13.6 Hz, 1H), 4.49(t, J=11.6 Hz, 1H), 4.15 (s, 1H), 3.44 (dd, J=16.0 Hz and 3.6 Hz, 1H),3.22-2.98 (m, 12H), 2.50-2.40 (m, 1H), 2.34-2.26 (m, 1H), 2.10-2.00 (m,1H), 1.91-1.80 (m, 1H), 1.80-1.50 (m, 9H), 1.44 (t, J=7.6 Hz, 3H),1.40-1.23 (m, 3H); MS (ESI) m/z 616.1 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.24 (s, 1H), 4.79 (d, J=13.6 Hz, 1H), 4.35(d, J=13.2 Hz, 1H), 4.13 (s, 1H), 3.60-3.37 (m, 4H), 3.16-2.94 (m, 8H),2.48-2.34 (m, 2H), 2.30-2.22 (m, 1H), 2.20-2.08 (m, 2H), 2.08-1.98 (m,1H), 1.85-1.71 (m, 1H), 1.70-1.57 (m, 2H), 1.06 (t, J=7.6 Hz, 3H); MS(ESI) m/z 560.4 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.23 (s, 1H), 4.68 (t, J=13.6 Hz, 1H), 4.39(t, J=14.0 Hz, 1H), 4.15 (s, 1H), 3.43-3.36 (m, 1H), 3.18-2.72 (m, 13H),2.46-2.38 (m, 1H), 2.30-2.25 (m, 1H), 1.80-1.60 (m, 4H), 0.99 (d, J=7.6Hz, 6H); MS (ESI) m/z 562.1 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.22 (s, 1H), 4.54 (s, 2H), 4.23 (s, 1H), 3.42(dd, J=16.0 Hz and 4.4 Hz, 1H), 3.26-2.97 (m, 12H), 2.48-2.38 (m, 1H),2.30-2.23 (m, 1H), 1.75-1.60 (m, 4H), 1.40 (t, J=7.6 Hz, 3H), 0.96 (t,J=7.2 Hz, 6H); MS (ESI) m/z 576.0 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.22 (s, 1H), 4.68 (t, J=13.6 Hz, 1H), 4.39(t, J=14.0 Hz, 1H), 4.13 (s, 1H), 3.40 (dd, J=16.0 Hz and 4.4 Hz, 1H),3.19-2.83 (m, 13H), 2.49-2.39 (m, 1H), 2.31-2.25 (m, 1H), 1.88-1.78 (m,2H), 1.71-1.60 (m, 1H), 1.50-1.39 (m, 2H), 1.01 (t, J=7.6 Hz, 3H); MS(ESI) m/z 548.0 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.17 (s, 1H), 4.46 (s, 2H), 4.06 (s, 1H),3.38-3.28 (m, 1H), 3.20-2.88 (m, 12H), 2.60-2.28 (m, 3H), 2.25-2.17 (m,1H), 2.11-2.00 (m, 1H), 1.98-1.90 (m, 1H), 1.90-1.78 (m, 3H), 1.64-1.50(m, 1H), 1.40-1.28 (m, 2H), 1.28-1.12 (m, 3H), 1.03-0.93 (m, 3H), 0.71(s, 3H); MS (ESI) m/z 642.2 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.25 (s, 1H), 4.48 (d, J=13.6 Hz, 1H), 4.29(d, J=13.6 Hz, 1H), 4.15 (s, 1H), 3.42 (dd, J=16.4 Hz and 4.4 Hz, 1H),3.18-2.87 (m, 9H), 2.47-2.35 (m, 1H), 2.32-2.16 (m, 2H), 1.99-1.60 (m,5H), 1.32-1.20 (m, 2H), 1.13 (s, 3H), 1.02 (s, 3H), 0.94 (s, 3H); MS(ESI) m/z 614.0 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.22 (s, 1H), 4.14 (s, 1H), 3.62-3.50 (m, 1H),3.48-3.38 (m, 1H), 3.20-2.78 (m, 12H), 2.60-2.49 (m, 1H), 2.48-2.35 (m,1H), 2.32-2.18 (m, 2H), 2.10-2.02 (m, 1H), 1.98-1.80 (m, 3H), 1.80-1.59(m, 2H), 1.28 (s, 3H), 1.05 (s 3H), 0.95 (s, 3H); MS (ESI) m/z 628.0(M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.19 (s, 1H), 4.55 (d, J=13.6 Hz, 1H), 4.29(d, J=13.6 Hz, 1H), 4.14 (s, 1H), 3.71-3.52 (m, 2H), 3.50-3.38 (m, 2H),3.25-2.94 (m, 9H), 2.58-2.37 (m, 2H), 2.38-2.24 (m, 2H), 2.09-1.82 (m,4H), 1.80-1.62 (m, 2H), 1.42 (s, 3H), 1.28 (s, 3H), 1.07 (s, 3H), 0.96(t, J=8.0 Hz, 3H); MS (ESI) m/z 642.0 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.16 (s, 1H), 4.38 (s, 2H), 4.13 (s, 1H), 3.41(dd, J=16.0 Hz and 4.4 Hz, 1H), 3.15-2.97 (m, 10H), 2.44-2.37 (m, 1H),2.30-2.22 (m, 1H), 2.04-1.92 (m, 1H), 1.88-1.78 (m, 2H), 1.78-1.48 (m,9H), 1.39-1.27 (m, 2H); MS (ESI) m/z 588.1 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.25 (s, 1H), 4.68 (t, J=13.2 Hz, 1H), 4.29(t, J=13.2 Hz, 1H), 4.16 (s, 1H), 3.80 (m, 1H), 3.44 (m, 1H), 3.20-2.90(m, 8H), 2.81 (s, 3H), 2.50-2.38 (m, 1H), 2.34-2.26 (m, 1H), 1.73-1.60(m, 1H), 1.52 (d, J=5.6 Hz, 3H), 1.47 (d, J=6.4 Hz, 1H); MS (ESI) m/z534.0 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.25 (s, 1H), 4.65 (t, J=13.2 Hz, 1H), 4.39(t, J=13.2 Hz, 1H), 4.16 (s, 1H), 3.91-3.82 (m, 1H), 3.45 (m, 1H),3.28-2.90 (m, 10H), 2.51-2.40 (m, 1H), 2.34-2.26 (m, 1H), 1.75-1.62 (m,1H), 1.61 (d, J=7.6 Hz, 3H), 1.45 (d, J=6.8 Hz, 3H), 1.37 (t, J=7.2 Hz,3H); MS (ESI) m/z 547.9 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.25 (s, 1H), 4.74 (t, J=13.6 Hz, 1H), 4.29(t, J=13.2 Hz, 1H), 4.16 (s, 1H), 3.50-3.39 (m, 2H), 3.20-2.97 (m, 8H),2.82 (s, 3H), 2.49-2.38 (m, 1H), 2.34-2.26 (m, 1H), 2.20 (m, 2H), 2.00(m, 2H), 1.80-1.55 (m, 4H), 1.52-1.38 (m, 2H), 1.35-1.25 (m, 1H); MS(ESI) m/z 574.0 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.25 (s, 1H), 4.64 (t, J=13.2 Hz, 1H), 4.51(t, J=13.2 Hz, 1H), 4.16 (s, 1H), 3.45 (dd, J=16.0 Hz and 4.4 Hz, 1H),3.22-2.90 (m, 12H), 2.51-2.42 (m, 1H), 2.35-2.26 (m, 1H), 1.96-1.64 (m,7H), 1.43 (t, J=7.2 Hz, 3H), 1.40-1.20 (m, 3H), 1.15-0.95 (m, 2H); MS(ESI) m/z 601.9 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.40-7.26 (m, 6H), 4.72-4.58 (m, 2H), 4.16 (s,1H), 3.52-2.39 (m, 5H), 3.21-2.88 (m, 10H), 2.50-2.39 (m, 1H), 2.35-2.26(m, 1H), 1.74-1.62 (m, 1H), 1.46 (t, J=7.2 Hz, 3H); MS (ESI) m/z 610.1(M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.51 (d, J=7.8 Hz, 2H), 7.41 (t, J=7.8 Hz,2H), 7.30 (br s, 1H), 7.05 (s, 1H), 4.41 (t, J=12.4 Hz, 1H), 4.23 (t,J=12.4 Hz, 1H), 3.75 (dd, J=31.2 Hz and 13.6 Hz, 2H), 3.40-3.30 (m, 1H),3.20-2.88 (m, 8H), 2.75 (s, 3H), 2.45-2.36 (m, 1H), 2.32-2.25 (m, 1H),1.72-1.60 (m, 1H), 1.58 (s, 3H), 1.49 (s, 3H); MS (ESI) m/z 624.1 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.38 (m, 2H), 7.31-7.28 (m, 4H), 4.81 (t,J=14.0 Hz, 1H), 4.68 (t, J=14.0 Hz, 1H), 4.16 (s, 1H), 3.60-3.49 (m,2H), 3.43 (dd, J=16.0 Hz and 4.4 Hz, 1H), 3.36-3.30 (m, 2H), 3.26-2.97(m, 10H), 2.49-2.39 (m, 1H), 2.34-2.26 (m, 1H), 1.73-1.62 (m, 1H),1.33-1.24 (m, 1H), 0.87-0.83 (m, 2H), 0.54-0.51 (m, 2H); MS (ESI) m/z636.0 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.48-7.42 (m, 2H), 7.42-7.33 (m, 2H),7.33-7.25 (m, 1H), 7.12-7.08 (m, 1H), 4.57-4.49 (m, 1H), 4.44-4.34 (m,1H), 4.16 (s, 1H), 3.91-3.82 (m, 1H), 3.66-3.58 (m, 1H), 3.36-3.28 (m,1H), 3.24-2.97 (m, 10H), 2.46-2.32 (m, 1H), 2.32-2.25 (m, 1H), 1.73-1.60(m, 1H), 1.55 (s, 3H), 1.44 and 1.42 (each s, total 3H), 1.30-1.18 (m,1H), 0.83-0.73 (m, 2H), 0.40-0.31 (m, 2H); MS (ESI) m/z 664.1 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.30 (s, 1H), 4.74-4.62 (m, 2H), 4.16 (s, 1H),3.45 (dd, J=12.4 Hz and 4.4 Hz, 1H), 3.39-3.31 (m, 1H), 3.28-3.22 (m,2H), 3.20-2.98 (m, 9H), 2.53-2.43 (m, 1H), 2.35-2.26 (m, 1H), 2.12-2.02(m, 1H), 1.92-1.82 (m, 1H), 1.80-1.45 (m, 10H), 1.40-1.18 (m, 3H),0.90-0.82 (m, 2H), 0.55-0.48 (m, 2H); MS (ESI) m/z 642.0 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.26 and 7.24 (each s, total 1H), 4.68-4.59(m, 1H), 4.58-4.46 (m, 1H), 4.15 (s, 1H), 3.75-3.63 (m, 1H), 3.48-3.37(m, 1H), 3.25-2.98 (m, 11H), 2.50-2.40 (m, 1H), 2.33-2.26 (m, 1H),2.12-1.92 (m, 1H), 1.85-1.60 (m, 2H), 1.54 and 1.44 (each d, J=6.8 Hz,total 3H), 1.18-1.02 (m, 4H), 0.82-0.73 (m, 2H), 0.50-0.38 (m, 2H); MS(ESI) m/z 588.1 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.31 and 7.24 (each s, total 1H), 4.75-4.64(m, 1H), 4.39-4.30 (m, 1H), 4.16 (s, 1H), 3.85-3.76 (m, 1H), 3.48-3.39(m, 1H), 3.26-2.98 (m, 10H), 2.50-2.12 (m, 3H), 1.73-1.62 (m, 1H), 1.44(d, J=6.4 Hz, 3H), 1.30-1.00 (m, 7H), 0.88-0.68 (m, 2H), 0.60-0.38 (m,2H); MS (ESI) m/z 602.1 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.30 (s, 1H), 4.70-4.50 (m, 2H), 4.14 (s, 1H),3.48-3.35 (m, 3H), 3.18-2.86 (m, 10H), 2.48-2.37 (m, 1H), 2.31-2.22 (m,1H), 1.71-1.58 (m, 1)

Hz, 3H), 1.06 (s, 9H); MS (ESI) m/z 576.1 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.34 (s, 1H), 4.77-4.66 (m, 2H), 4.14 (s, 1H),3.49-3.38 (m, 2H), 3.32-3.18 (m, 1H), 3.18-2.94 (m, 10H), 2.50-2.37 (m,1H), 2.30-2.22 (m, 1H), 1.71-1.60 (m, 1H), 1.38-1.28 (m, 1H), 1.03 (s,9H), 0.90-0.74 (m, 2H), 0.55-0.44 (m, 2H); MS (ESI) m/z 602.1 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.26 (s, 1H), 4.50 and 4.38 (each d, J=13.6Hz, total 1H), 4.16 (s, 1H), 3.52-3.35 (m, 4H), 3.20-2.98 (m, 9H),2.50-2.40 (m, 1H), 2.34-2.26 (m, 1H), 1.75-1.62 (m, 1H), 1.58 and 1.53(each d, J=6.4 Hz, total 3H), 1.38 and 1.29 (each t, J=7.2 Hz, total3H), 0.96-0.78 (m, 2H), 0.72-0.40 (m, 2); MS (ESI) m/z 574.1 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.28 and 7.25 (each s, total 1H), 4.76-4.72(m, 1H), 4.47-4.40 (m, 1H), 4.14 (s, 1H), 3.57-3.35 (m, 3H), 3.20-2.98(m, 10H), 2.50-2.40 (m, 1H), 2.33-2.26 (m, 1H), 1.74-1.62 (m, 1H), 1.51(t, J=7.2 Hz, 3H), 1.45-1.22 (m, 1H), 1.22-1.16 and 1.05-0.95 (each m,total 1H), 0.90-0.60 (m, 5H), 0.60-0.34 (m, 3H); MS (ESI) m/z 600.1(M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.15 (s, 1H), 6.36 (tt, J=53.6 Hz and 3.2 Hz,1H), 4.50 (s, 2H), 4.12 (s, 1H), 3.71 (dt, J=15.2 Hz and 3.2 Hz, 2H),3.41 (dd, J=16.0 Hz and 4.8 Hz, 1H), 3.15-2.95 (m, 8H), 2.46-2.38 (m,1H), 2.30-2.22 (m, 1H), 1.72-1.61 (m, 1H); MS (ESI) m/z 542.0 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.23 (s, 1H), 6.50 (tt, J=53.6 Hz and 3.2 Hz,1H), 4.65 (s, 2H), 4.12 (s, 1H), 3.90-3.80 (m, 2H), 3.44-3.38 (m, 1H),3.16-2.95 (m, 11H), 2.47-2.40 (m, 1H), 2.30-2.23 (m, 1H), 1.71-1.61 (m,1H), MS (ESI) m/z 556.0 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.24 (s, 1H), 6.51 (br t, J=55.2 Hz, 1H), 4.68(dd, J=16.8 Hz and 14.8 Hz, 2H), 4.13 (s, 1H), 3.86-3.76 (m, 2H),3.48-3.39 (m, 3H), 3.18-2.95 (m, 8H), 2.47-2.39 (m, 1H), 2.30-2.24 (m,1H), 1.71-1.60 (m, 1H), 1.44 (t, J=7.2 Hz, 3H); MS (ESI) m/z 570.0(M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.56-7.48 (m, 5H), 7.10 (s, 1H), 4.37 (br s,4H), 4.12 (s, 1H), 3.38 (dd, J=16.0 Hz and 4.4 Hz, 1H), 3.14-2.95 (m,8H), 2.43-2.35 (m, 1H), 2.27-2.22 (m, 1H), 1.70-1.69 (m, 1H); MS (ESI)m/z 568.3 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.22 (s, 1H), 4.89-4.83 (m, 1H), 4.17-4.10 (m,2H), 3.47-3.37 (m, 1H), 3.18-2.95 (m, 8H), 2.76-2.72 (m, 3H), 2.48-2.22(m, 3H), 2.04-1.95 (m, 1H), 1.91-1.70 (m, 5H), 1.70-1.50 (m, 6H),1.33-1.20 (m, 1H); MS (ESI) m/z 588.4 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.21 (s, 1H), 4.58-4.48 (m, 2H), 4.13 (s, 1H),3.42 (dd, J=16.0 Hz and 4.0 Hz, 1H), 3.23-2.95 (m, 12H), 2.46-2.39 (m,1H), 2.30-2.27 (m, 1H), 1.88-1.78 (m, 2H), 1.70-1.60 (m, 1H), 1.47-1.36(m, 5H), 0.98 (t, J=6.8 Hz, 3H); MS (ESI) m/z 562.1 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.27 (s, 1H), 4.44-4.15 (m, 5H), 3.90-3.76 (m,2H), 3.16-2.88 (m, 10H), 3.00 (s, 3H), 2.51-2.28 (m, 4H), 1.75-1.65 (m,1H); MS (ESI) m/z 562.3 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.25 (s, 1H), 4.65-4.15 (m, 7H), 3.86 (s, 1H),3.78-3.71 (m, 1H), 3.16-3.00 (m, 10H), 2.52-2.28 (m, 4H), 1.75-1.65 (m,1H), 1.44 (s, 3H); MS (ESI) m/z 576.3 (M+H).

¹H NMR (400 MHz, CD₃OD) δ7.14 (s, 1H), 4.37 (s, 2H), 4.13 (s, 1H), 3.40(dd, J=16.0 Hz and 4.0 Hz, 1H), 3.17-2.97 (m, 10H), 2.45-2.35 (m, 1H),2.30-2.23 (m, 1H), 1.77-1.64 (m, 3H), 1.48-1.43 (m, 2H), 1.00 (t, J=7.2Hz, 3H); MS (ESI) m/z 534.0 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.13 (s, 1H), 4.34 (s, 2H), 4.13 (s, 1H), 3.40(dd, J=16.0 Hz and 4.4 Hz, 1H), 3.19-2.97 (m, 10H), 2.46-2.36 (m, 1H),2.28-2.18 (m, 3H), 2.05-1.94 (m, 1H), 1.92-1.86 (m, 4H), 1.74-1.59 (m,1H); MS (ESI) m/z 546.0 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.32-7.15 (m, 5H), 7.07 (s, 1H), 4.35 (s, 2H),4.04 (s, 1H), 3.35-3.25 (m, 3H), 3.08-2.88 (m, 10H), 2.40-2.30 (m, 1H),2.24-2.14 (m, 1H), 1.65-1.54 (m, 1H); MS (ESI) m/z 582.0 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.20 (s, 1H), 4.42 (s, 2H), 4.14 (s, 1H),3.47-3.40 (m, 1H), 3.18-2.97 (m, 9H), 2.49-2.39 (m, 1H), 2.32-2.20 (m,2H), 1.74-1.63 (m, 1H), 1.37 (d, J=6.8 Hz, 3H), 1.09 (d, J=6.8 Hz, 3H),1.04 (d, J=6.8 Hz, 3H); MS (ESI) m/z 547.9 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.27 and 7.24 (each s, total 1H), 4.76-4.70(m, 1H), 4.46-4.41 and 4.27-4.15 (each m, total 1H), 4.15 (s, 1H),3.47-3.33 (m, 2H), 3.20-2.97 (m, 8H), 2.85 (s, 3H), 2.49-2.41 (m, 1H),2.38-2.26 (m, 1H), 2.25-2.12 (m, 1H), 1.72-1.63 (m, 1H), 1.47 and 1.42(each d, J=6.8 Hz, total 3H), 1.20 and 1.06 (each d, J=6.4 Hz, total3H), 1.13-1.09 (m, 3H); MS (ESI) m/z 562.1 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.26 and 7.23 (each s, total 1H), 4.72-4.67(m, 1H), 4.55 and 4.31 (each d, J=14.0 Hz, total 1H), 4.15 (s, 1H),3.46-3.30 (m, 3H), 3.20-2.97 (m, 9H), 2.48-2.40 (m, 1H), 2.38-2.26 (m,2H), 1.72-1.62 (m, 1H), 1.44-1.31 (m, 6H), 1.19-1.13 (m, 3H), 1.09-1.05(m, 3H); MS (ESI) m/z 576.2 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.29 (s, 1H), 4.60-4.42 (m, 2H), 4.13 (s, 1H),3.60-3.51 (m, 1H), 3.46-3.38 (m, 1H), 3.25-2.86 (m, 11H), 2.48-2.38 (m,1H), 2.32-2.24 (m, 1H), 2.06-1.94 (m, 1H), 1.90-1.80 (m, 1H), 1.70-1.53(m, 2H), 1.53-1.43 (m, 1H), 1.13 (s, 3H), 1.03 (s, 3H); MS (ESI) m/z574.0 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.21 (s, 1H), 4.69 (t, J=13.2 Hz, 1H), 4.35(t, J=13.2 Hz, 1H), 4.13 (s, 1H), 3.47-3.36 (m, 2H), 3.20-2.95 (m, 10H),2.46-2.39 (m, 1H), 2.29-2.26 (m, 1H), 2.20-2.10 (m, 2H), 2.01-1.92 (m,2H), 1.82-1.58 (m, 4H), 1.50-1.37 (m, 2H), 1.34 (t, J=7.2 Hz, 3H),1.34-1.25 (m, 1H); MS (ESI) m/z 588.2 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.24 (s, 1H), 4.70 (t, J=13.2 Hz, 1H), 4.39(t, J=13.2 Hz, 1H), 4.15 (s, 1H), 3.47-3.30 (m, 2H), 3.20-2.95 (m, 9H),2.88 (s, 3H), 2.48-2.40 (m, 1H), 2.31-2.26 (m, 1H), 1.77 (t, J=8.4 Hz,2H), 1.73-1.61 (m, 1H), 1.01 (s, 9H); MS (ESI) m/z 576.3 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.24 (s, 1H), 4.60-4.55 (m, 2H), 4.14 (s, 1H),3.47-3.42 (m, 1H), 3.20-2.96 (m, 12H), 2.52-2.43 (m, 1H), 2.33-2.26 (m,1H), 1.77-1.65 (m, 3H), 1.42 (t, J=6.8 Hz, 3H), 1.00 (s, 9H); MS (ESI)m/z 590.3 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.33 (s, 1H), 4.60-4.50 (m, 2H), 4.11 (s, 1H),3.80-3.64 (m, 4H), 3.45-3.36 (m, 1H), 3.15-2.88 (m, 9H), 2.65 (s, 6H),2.48-2.38 (m, 1H), 2.28-2.21 (m, 1H), 2.12 (br s, 4H), 1.71-1.60 (m,1H); MS (ESI) m/z 589.2

¹H NMR (400 MHz, CD₃OD) δ 7.36 (s, 1H), 4.60-4.52 (m, 1H), 4.14 (s, 1H),3.82-3.60 (m, 4H), 3.46-3.38 (m, 1H), 3.20-2.96 (m, 9H), 2.68 (s, 6H),2.52-2.40 (m, 1H), 2.30-2.24 (m, 1H), 2.20-2.09 (m, 4H), 1.48-1.40 (m,3H); MS (ESI) m/z 603.4 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.21 (s, 1H), 4.58-4.48 (m, 2H), 4.13 (s, 1H),3.42 (dd, J=16.4 Hz and 4.4 Hz, 2H), 3.20-2.96 (m, 11H), 2.48-2.38 (m,1H), 2.31-2.23 (m, 1H), 1.90-1.77 (m, 2H), 1.72-1.60 (m, 1H), 1.39 (t,J=7.2 Hz, 3H), 1.02 (t, J=7.2 Hz, 3H); MS (ESI) m/z 548.3 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.17 (s, 1H), 4.58-4.50 (m, 1H), 4.43-4.36 (m,1H), 4.13 (s, 1H), 3.42 (dd, J=16.0 Hz and 4.4 Hz, 1H), 3.20-2.93 (m,9H), 2.85-2.77 (m, 1H), 2.46-2.36 (m, 1H), 2.30-2.26 (m, 1H), 1.70-1.60(m, 1H), 1.50 (d, J=6.8 Hz, 3H), 1.13-1.04 (m, 1H), 0.88-0.70 (m, 2H),0.68-0.59 (m, 1H), 0.43-0.36 (m, 1H); MS (ESI) m/z 546.1 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.20 (s, 1H), 4.36-4.24 (m, 2H), 4.10 (s, 1H),3.42-3.35 (m, 1H), 3.12-2.77 (m, 12H), 2.47-2.38 (m, 1H), 2.27-2.23 (m,1H), 1.69-1.59 (m, 1H), 1.57-1.49 (br s, 3H), 1.33-1.25 and 1.20-1.10(each m, total 1H), 0.88-0.73 (m, 2H), 0.72-0.66 and 0.60-0.52 (each m,total 1H), 0.48-0.35 (m, 1H); MS (ESI) m/z 560.4 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.13 (s, 1H), 4.49 (s, 2H), 4.13 (s, 1H), 3.41(dd, J=16.0 Hz and 4.4 Hz, 1H), 3.16-2.84 (m, 9H), 2.44-2.37 (m, 1H),2.28-2.25 (m, 1H), 1.70-1.60 (m, 1H), 0.97-0.93 (m, 4H); MS (ESI) m/z518.2 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.17 and 7.24 (each s, total 1H), 4.74, 4.67,4.53 and 4.35 (each d, J=13.6 Hz, total 2H), 4.15 (s, 1H), 3.49-3.36 (m,3H), 3.20-2.90 (m, 9H), 2.50-2.40 (m, 1H), 2.40-2.28 (m, 2H), 1.73-1.64(m, 1H), 1.47-1.30 (m, 6H), 1.20-1.12 (m, 3H), 1.10-1.05 (m, 3H); MS(ESI) m/z 576.2 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.28 (s, 1H), 4.77-4.70 (m, 1H), 4.51-4.44 (m,1H), 4.12 (s, 1H), 3.54-3.38 (m, 2H), 3.18-2.85 (m, 9H), 2.48-2.38 (m,1H), 2.27-2.24 (m, 1H), 2.02-1.90 (m, 2H), 1.70-1.60 (m, 1H), 1.54 (s,3H), 1.53 (s, 3H), 1.13-1.05 (m, 6H); MS (ESI) m/z 576.2 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.80-7.76 (m, 2H), 7.58-7.48 (m, 3H),6.97-6.96 (m, 1H), 4.41-4.35 (m, 1H), 4.09-4.03 (m, 2H), 3.15-2.90 (m,9H), 2.90-2.80 (m, 3H), 2.36-2.28 (m, 1H), 2.25-2.18 (m, 1H), 1.98 (s,3H), 1.95 (s, 3H), 1.65-1.55 (m, 1H); MS (ESI) m/z 610.1 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.41 (s, 1H), 4.85-4.58 (m, 2H), 4.13 (s, 1H),3.87-3.60 (m, 7H), 3.42 (dd, J=16.0 Hz and 4.0 Hz, 1H), 3.20-3.10 (m,3H), 3.09-2.95 (m, 8H), 2.47-2.39 (m, 1H), 2.28-2.24 (m, 1H), 2.20-2.00(m, 4H), 1.71-1.60 (m, 1H), 1.35-1.23 (m, 1H), 0.87-0.80 (m, 2H),0.57-0.49 (m, 2H); MS (ESI) m/z 629.2

¹H NMR (400 MHz, CD₃OD) δ 7.21 (s, 1H), 4.73-4.64 (m, 1H), 4.57-4.48 (m,1H), 4.12 (s, 1H), 3.44-3.34 (m, 2H), 3.25-2.95 (m, 11H), 2.50-2.38 (m,1H), 2.30-2.21 (m, 1H), 1.71-1.60 (m, 1H), 1.42-1.36 (m, 3H), 1.25-1.15(m, 1H), 0.84-0.77 (m, 2H), 0.50-0.42 (m, 2H); MS (ESI) m/z 560.3 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.29 and 7.22 (each s, total 1H), 4.73-4.68(m, 2H), 4.11 (s, 1H), 3.45-3.35 (m, 1H), 3.20-2.90 (m, 12H), 2.49-2.40(m, 1H), 2.30-2.21 (m, 1H), 1.71-1.60 (m, 1H), 0.82-0.77 (m, 4H),0.50-0.39 (m, 4H); MS (ESI) m/z 586.1 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.23 (s, 1H), 4.51-4.44 (m, 1H), 4.20-4.13 (m,2H), 3.46-3.39 (m, 1H), 3.18-2.95 (m, 8H), 2.71-2.58 (m, 4H), 2.58-2.37(m, 2H), 2.30-2.22 (m, 2H), 2.10-2.02 (m, 1H), 2.00-1.87 (m, 2H),1.70-1.59 (m, 4H); MS (ESI) m/z 560.1 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.32 (s, 1H), 4.78-4.71 (m, 1H), 4.51-4.44 (m,1H), 4.14 (s, 1H), 3.62-3.50 (m, 1H), 3.48-3.37 (m, 1H), 3.30-2.95 (m,9H), 2.49-2.36 (m, 1H), 2.30-2.26 (m, 1H), 1.99-1.90 (m, 2H), 1.77-1.58(m, 7H), 1.17-1.07 (m, 12H); MS (ESI) m/z 618.1 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.21 (s, 1H), 4.54-4.47 (m, 2H), 4.08 (s, 1H),3.55-3.47 (m, 2H), 3.37 (dd, J=16.4 Hz and 4.8 Hz, 1H), 3.11-2.89 (m,10H), 2.41-2.34 (m, 1H), 2.20-2.13 (m, 3H), 1.65-1.54 (m, 1H), 1.20-1.16(m, 2H), 0.50-0.41 (m, 4H); MS (ESI) m/z 572.2 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.11 (s, 1H), 4.46 (s, 2H), 4.15-4.07 (m, 2H),3.35 (dd, J=16.4 Hz and 4.8 Hz, 1H), 3.10-2.89 (m, 9H), 2.40-2.32 (m,1H), 2.27-2.17 (m, 1H), 1.65-1.55 (m, 1H); MS (ESI) m/z 560.1 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.13 (s, 1H), 4.10 (s, 3H), 3.62-3.55 (m, 2H),3.40 (dd, J=16.0 Hz and 4.4 Hz, 1H), 3.10-2.95 (m, 8H), 2.62 (s, 3H),2.41-2.32 (m, 1H), 2.27-2.20 (m, 1H), 1.69-1.59 (m, 1H); MS (ESI) m/z574.0 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.10 (s, 1H), 4.09 (s, 2H), 4.05 (s, 1H),3.58-3.50 (m, 2H), 3.33 (dd, J=16.4 Hz and 4.8 Hz, 1H), 3.05-2.85 (m,10H), 2.33-2.25 (m, 1H), 2.20-2.14 (m, 1H), 1.63-1.53 (m, 1H), 1.13 (t,J=6.8 Hz, 3H); MS (ESI) m/z 588.1 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.27 (s, 1H), 4.78-4.69 (m, 2H), 4.15 (s, 1H),4.07-4.01 (m, 2H), 3.85-3.81 (m, 2H), 3.41 (dd, J=16.0 Hz and 4.4 Hz,1H), 3.17-2.95 (m, 8H), 2.76-2.66 (m, 2H), 2.43-2.36 (m, 1H), 2.31-2.27(m, 1H), 1.70-1.60 (m, 1H); MS (ESI) m/z 568.0 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.61-7.51 (m, 5H), 7.15 and 7.07 (each s,total 1H), 4.71-4.58 (m, 1H), 4.18-4.00 (m, 2H), 3.12-2.70 (m, 13H),2.40-2.18 (m, 2H), 1.86 (br s, 3H), 1.66-1.52 (m, 1H); MS (ESI) m/z596.1 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.61-7.50 (m, 5H), 7.03, 6.99 and 6.97 (eachs, total 1H), 5.02-4.96 (m, 1H), 4.78-4.70 (m, 1H), 4.45-4.35 (m, 1H),4.34-4.20 (m, 1H), 4.10 (s, 1H), 3.49-3.38 (m, 1H), 3.20-2.91 (m, 8H),2.37-2.30 (m, 1H), 2.23-2.20 (m, 1H), 1.81 (d, J=6.0 Hz, 3H), 1.65-1.52(m, 1H), 1.48-1.35 (m, 3H); MS (ESI) m/z 610.2 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.11 (s, 1H), 4.45 (s, 2H), 4.09 (s, 1H),3.42-3.35 (m, 1H), 3.12-2.93 (m, 8H), 2.43-2.36 (m, 1H), 2.25-2.22 (m,1H), 1.68-1.55 (m, 4H), 1.15-1.12 (m, 2H), 0.90-0.87 (m, 2H); MS (ESI)m/z 532.1 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.23 (s, 1H), 4.73-4.64 (m, 2H), 4.12 (s, 1H),3.54-3.38 (m, 2H), 3.18-2.85 (m, 9H), 2.49-2.38 (m, 1H), 2.28-2.24 (m,1H), 1.70-1.57 (m, 4H), 1.39 (t, J=7.2 Hz, 3H), 1.05-0.89 (m, 4H); MS(ESI) m/z 560.1 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.21 (s, 1H), 4.54-4.47 (m, 2H), 4.12 (s, 1H),3.39 (dd, J=16.0 Hz and 4.4 Hz, 1H), 3.15-2.85 (m, 14H), 2.44-2.37 (m,1H), 2.28-2.22 (m, 1H), 1.70-1.59 (m, 1H); MS (ESI) m/z 506.1 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.25-7.201 (s, 1H), 4.55-4.40 (m, 2H), H),4.29-4.25 (m, 1H), 4.13 (s, 1H), 3.50-3.42 (m, 2H), 3.20-2.88 (m, 10H),2.48-2.40 (m, 1H), 2.30-2.24 (m, 1H), 2.10-2.00 (m, 1H), 1.91-1.62 (m,6H), 1.59 and 1.52 (each d, J=6.4 Hz, total 3H) 1.70-1.59 (1H); MS (ESI)m/z 506.1 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.31-7.18 (m, 5H), 4.45 (s, 2H), 4.26 (m, 1H),4.12 (s, 1H), 3.50 (dd, J=16.4 Hz and 7.6 Hz, 2H), 3.23 (dd, J=16.8 Hzand 6.4 Hz, 2H), 3.05-2.97 (m, 9H), 2.45-2.25 (m, 2H), 1.70-1.60 (m,1H); MS (ESI) m/z 594.2 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.28 (s, 1H), 4.63 (d, J=11.2 Hz, 2H), 4.13(s, 1H), 3.68-3.64 (m, 1H), 3.52-3.51 (m, 1H), 3.43-3.42 (m, 2H),3.12-2.89 (m, 9H), 2.59 (s, 1H), 2.43-2.37 (m, 2H), 2.28-2.26 (m, 1H)1.76-1.43 (m, 9H); MS (ESI) m/z 586.2 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.19 (s, 1H), 4.43 (s, 2H), 4.14 (s, 1H),3.11-2.97 (m, 11H), 2.44-2.41 (m, 1H), 2.29-2.26 (m, 1H), 1.70-1.64 (m,1H), 1.51-1.41 (m, 10H), 1.08 (s, 3H); MS (ESI) m/z 558.3 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.14 (s, 1H), 4.39 (s, 2H), 4.12 (s, 1H),3.21-2.97 (m, 11H), 2.45-2.41 (m, 1H), 2.28-2.25 (m, 1H), 1.69-1.66 (m,3H), 0.99 (s, 9H); MS (ESI) m/z 562.3 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.14 (s, 1H), 4.36 (s, 2H), 4.11 (s, 1H),3.54-3.51 (m, 1H) 3.12-2.97 (m, 9H), 2.45-2.38 (m, 1H), 2.28-2.25 (m,1H), 1.67-1.64 (m, 1H), 1.43 (d, J=6.4 Hz, 6H); MS (ESI) m/z 519.9(M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.26 (s, 1H), 4.57-4.47 (m, 2H), 4.14 (s, 1H),3.43-3.39 (m, 2H), 3.21-2.95 (m, 11H), 2.46-2.38 (m, 1H), 2.29-2.26 (m,1H), 2.05-1.85 (m, 6H), 1.82-1.72 (m, 2H), 1.70-1.60 (m, 1H), 1.46 (t,J=7.2 Hz, 3H), 0.87 (t, J=6.8 Hz, 3H); MS (ESI) m/z 602.1 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.24 and 7.12 (each s, total 1H), 4.75-4.70,4.54-4.44 and 4.34-4.27 (each m, total 2H), 4.03 (s, 1H), 3.55-3.46 (m,1H), 3.40-3.26 (m, 1H), 3.18-2.85 (m, 10H), 2.40-2.30 (m, 1H), 2.20-2.14(m, 1H), 1.61-1.52 (m, 1H), 1.49 and 1.25 (each t, J=6.8 Hz, total 3H),1.40 and 1.35 (each d, J=7.2 Hz, total 3H), 1.16 (s, 3H), 0.99 (s, 3H),0.85 (s, 3H); MS (ESI) m/z 590.4 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.15 (s, 1H), 4.52 (br s, 2H), 4.03 (s, 1H),3.55 (s, 1H), 3.35-3.30 (m, 3H), 3.03-2.88 (m, 9H), 2.38-2.30 (m, 1H),2.19-2.15 (m, 1H), 1.93-1.77 (m, 2H)

(m, 5H), 0.83-0.79 (m, 6H); MS (ESI) m/z 588.0 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.32 (s, 4H), 7.12 (s, 1H), 4.74-4.72 (m, 6H),4.03 (s, 1H), 3.39-3.31 (m, 1H), 3.05-2.90 (m, 8H), 2.19-2.16 (m, 1H),1.61-1.53 (m, 1H); MS (ESI) m/z 580.0 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.05 (s, 1H), 4.35 (s, 2H), 4.04 (s, 1H),3.69-3.61 (m, 3H), 3.36-3.24 (m, 3H), 3.03-2.81 (m, 8H), 2.38-2.30 (m,1H), 2.17-2.16 (m, 1H), 1.63-1.53 (m, 1H), 1.14-1.12 (m, 6H); MS (ESI)m/z 564.1 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.46-7.42 (m, 5H), 6.97 (s, 1H), 4.49-4.47 (m,1H), 4.16-3.97 (m, 2H), 2.99-2.88 (m, 10H), 2.32-2.25 (m, 2H), 1.95-1.94(m, 1H), 1.69-1.67 (m, 3H), 1.57-1.52 (m, 1H); MS (ESI) m/z 582.4 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.08 (s, 1H), 4.31 (s, 2H), 4.05 (s, 1H),3.36-3.31 (m, 2H), 3.12-2.91 (m, 9H), 2.47-2.36 (m, 3H), 2.33-2.29 (m,1H), 2.08-1.86 (m, 5H), 1.60-1.53 (m, 2H), 1.25-1.14 (s, 3H), 1.05-0.91(s, 3H); MS (ESI) m/z 614.1 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.27-7.16 (m, 6H), 4.70-4.63 (m, 1H),4.41-4.34 (m, 1H), 4.06 (s, 1H), 3.48-3.41 (m, 2H), 3.33-3.29 (m, 1H)),3.12-2.80 (m, 13H), 2.35-2.28 (m, 1H), 2.20-2.17 (m, 1H), 1.61-1.51 (m,1H); MS (ESI) m/z 596.0 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.26 (s, 1H), 4.74 (m, 1H), 4.42 (m, 1H), 4.15(s, 1H), 3.97-3.89 (m, 2H), 3.80-3.77 (m, 1H), 3.53 (m, 1H), 3.39 (s,3H), 3.13-2.88 (m, 12H), 2.46-2.38 (m, 1H), 2.29-2.26 (m, 2H), 1.71-1.64(m, 2H); MS (ESI) m/z 576.1 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.24 (s, 1H), 4.64-4.53 (m, 2H), 4.13 (s, 1H),3.96-3.87 (m, 2H), 3.77-3.75 (m, 1H), 3.52-3.34 (m, 5H), 3.22-2.79 (m,10H), 2.48-2.40 (m, 1H), 2.28-2.26 (m, 2H), 1.71-1.65 (m, 2H), 1.44-1.41(m, 3H); MS (ESI) m/z 590.1 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.15 and 7.14 (each s, total 1H), 4.59-4.54(m, 1H), 4.24-4.15 (m, 1H), 4.05 (s, 1H), 3.39-3.30 (m, 2H), 3.03-2.88(m, 8H), 2.70 (s, 3H), 2.37-2.29 (m, 1H), 2.20-2.17 (m, 1H), 1.95-1.88(m, 1H), 1.70-1.52 (m, 2H), 1.40-1.34 (m, 3H), 0.01-0.95 (m, 3H); MS(ESI) m/z 548.0 (M+H).

¹H NMR (400 MHz, CD₃OD) δ7.12 and 7.10 (each s, total 1H), 4.53 (m, 1H),4.28-4.26 (m, 1H), 4.03 (s, 1H), 3.41-3.35 (m, 3H), 3.03-2.87 (m, 9H),2.39-2.31 (m, 1H), 2.18-2.15 (m, 1H), 1.91 (m, 1H), 1.71-1.52 (m, 2H),1.43-1.23 (m, 6H); 0.99-0.95 (m, 3H); MS (ESI) m/z 562.1 (M+H)

¹H NMR (400 MHz, CD₃OD) δ 7.13 (s, 1H), 4.33 (s, 2H), 4.04 (s, 1H),3.40-3.30 (m, 2H), 3.12-2.88 (m, 9H), 2.32-2.18 (m, 2H), 1.77-1.71 (m,2H), 1.53-1.50 (m, 2H), 1.33-1.20 (m, 3H), 0.95 (s, 3H), 0.84 (d, J=9.6Hz, 6H); MS (ESI) m/z 614.4 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.17 (s, 1H), 4.80-4.61 (m, 2H), 4.04 (s, 1H),3.37-3.27 (m, 1H), 3.09-2.85 (m, 11H), 2.38-2.27 (m, 1H), 2.22-2.15 (m,1H), 1.66-1.50 (m, 2H), 1.22-1.04 (m, 4H), 0.92-0.81 (m, 1H), 0.78-0.65(m, 3H); MS (ESI) m+572.2 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.19 (s, 1H), 4.80-4.62 (m, 2H), 4.05 (s, 1H),3.73-3.60 (m, 1H), 3.42-3.28 (m, 2H), 3.10-2.85 (m, 8H), 2.40-2.27 (m,1H), 2.22-2.15 (m, 1H), 1.62-1.50 (m, 2H), 1.35-1.15 (m, 4H), 0.97-0.78(m, 2H), 0.78-0.60 (m, 3H), 0.35-0.27 (m, 2H); MS (ESI) m/z 586.2 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.17 (s, 1H), 4.93 (br s, 2H), 4.74-4.39 (m,2H), 3.65 (br d, J=27.2 Hz, 2H), 3.36 (dd, J=16.4 Hz and 4.4 Hz, 1H),3.10-2.89 (m, 11H), 2.43-2.35 (m, 1H), 2.25-2.17 (m, 1H), 1.66-1.55 (m,1H); MS (ESI) m/z 537.9 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.24 (s, 1H), 4.74-4.68 (m, 1H), 4.59-4.54 (m,1H), 4.13 (s, 1H), 4.08-4.04 (m, 1H), 3.42 (dd, J=16.4 Hz and 4.4 Hz,1H), 3.18-2.94 (m, 10H), 2.47-2.40 (m, 1H), 2.31-2.08 (m, 3H), 2.05-1.92(m, 1H), 1.90-1.79 (m, 3H), 1.78-1.60 (m, 3H), 1.20-1.09 (m, 1H),0.82-0.70 (m, 2H), 0.45-0.36 (m, 2H); MS (ESI) m/z 600.0 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.31-7.18 (m, 5H), 4.70-4.48 (m, 3H), 4.12 (s,1H), 3.55-3.35 (m, 5H), 3.18-2.93 (m, 10H), 2.45-2.37 (m, 1H), 2.30-2.20(m, 1H), 1.70-1.58 (m, 1H), 1.23-1.10 (m, 1H), 0.82-0.70 (m, 2H),0.43-0.36 (m, 2H); MS (ESI) m/z 648.1 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.29 and 7.26 (each s, total 1H), 4.85-4.73(m, 1H), 4.14 (s, 1H), 3.80-3.73 (m, 1H), 3.62-3.52 (m, 1H), 3.48-3.38(m, 1H), 3.25-2.86 (m, 9H), 2.50-2.36 (m, 1H), 2.30-2.22 (m, 1H),1.78-1.60 (m, 2H), 1.55-1.36 (m, 1H), 1.27-1.13 (m, 1H), 1.05-0.68 (m,8H), 0.52-0.28 (m, 4H); MS (ESI) m/z 612.1 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.30 (s, 1H), 4.70-4.57 (m, 2H), 4.13 (s, 1H),3.58-3.55 (m, 1H), 3.44-3.39 (m, 1H), 3.26-2.95 (m, 11H), 2.48-2.37 (m,1H), 2.31-2.24 (m, 1H), 2.15-1.72 (m, 7H), 1.71-1.59 (m, 1H), 1.35-1.24(m, 3H), 0.90-0.79 (m, 4H), 0.55-0.44 (m, 2H); MS (ESI) m 627.9 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.29 and 7.24 (each s, total 1H), 4.20-4.08(m, 3H), 3.93-3.57 (m, 3H), 3.48-3.38 (m, 2H), 3.21-2.89 (m, 9H),2.50-2.40 (m, 1H), 2.32-2.26 (m, 1H), 1.75-1.60 (m, 1H), 1.68-1.58 and1.44-1.36 (each m, total 3H), 1.31 and 1.01 (each s, total 9H); MS (ESI)m/z 606.1 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.07 (s, 1H), 4.64 (s, 2H), 4.57-4.09 (m, 6H),3.39 (dd, J=16.0 Hz and 4.4 Hz, 1H), 3.35 (s, 3H), 3.15-2.95 (m, 8H),2.47-2.37 (m, 1H), 2.28-2.22 (m, 1H), 1.70-1.57 (m, 1H); MS (ESI) m/z548.4 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.22 (s, 1H), 4.72 (t, J=12.8 Hz, 1H), 4.33(t, J=12.4 Hz, 1H), 4.13 (s, 1H), 3.88-3.79 (m, 1H), 3.45-3.37 (m, 1H),3.18-2.73 (m, 11H), 2.48-2.36 (m, 1H), 2.36-2.14 (m, 3H), 1.98-1.82 (m,4H), 1.78-1.60 (m, 3H); MS (ESI) m/z 560.0 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.22 (s, 1H), 4.62-4.46 (m, 2H), 4.23 (s, 1H),4.42-4.35 (m, 1H), 3.43-3.37 (m, 1H), 3.25-2.95 (m, 10H), 2.45-2.37 (m,1H), 2.31-2.14 (m, 3H), 2.00-1.80 (m, 4H), 1.79-1.60 (m, 3H), 1.36 (t,J=6.8 Hz, 3H); MS (ESI) m/z 574.1 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.43-7.28 (m, 5H), 7.00 (s, 1H), 7.28 (s, 2H),7.11 (s, 1H), 3.41 (s, 2H), 3.15-2.95 (m, 9H), 2.41-2.33 (m, 1H),2.26-2.23 (m, 1H), 1.60-1.59 (m, 1H), 1.46 (s, 6H); MS (ESI) m/z 610.0(M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.55-7.27 (m, 5H), 6.96 and 6.94 (each s,total 1H), 4.30-4.18 (m, 2H), 4.12 (s, 1H), 3.75-3.69 (m, 1H), 3.63-3.56(m, 1H), 3.34 (s, 2H), 3.24-2.86 (m, 9H), 2.42-2.30 (m, 1H), 2.27-2.23(m, 1H), 1.69-1.59 (m, 1H), 1.54 (s, 3H), 1.45 (s, 3H), 1.38-1.32 (m,3H); MS (ESI) m/z 638.1 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.13 (s, 1H), 4.37 (s, 2H), 4.11 (s, 1H), 3.41(dd, J=16.4 Hz and 4.4 Hz, 1H), 3.15-2.95 (m, 10H), 2.45-2.37 (m, 1H),2.29-2.24 (m, 1H), 1.84-1.74 (m, 2H), 1.70-1.60 (m, 1H), 1.05 (t, J=6.8Hz, 3H); MS (ESI) m/z 519.9 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.22 (s, 1H), 4.66 (t, J=13.6 Hz, 1H), 4.38(t, J=12.8 Hz, 1H), 4.13 (s, 1H), 3.41 (dd, J=16.0 Hz and 4.0 Hz, 1H),3.30-2.95 (m, 10H), 2.86 (s, 3H), 2.45-2.38 (m, 1H), 2.30-2.24 (m, 1H),1.91-1.80 (m, 2H), 1.70-1.60 (m, 1H), 1.03 (t, J=7.2 Hz, 3H); MS (ESI)m/z 534.0 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.23 (s, 1H), 4.55 (t, J=14.4 Hz, 1H), 4.38(t, J=14.4 Hz, 1H), 4.14 (s, 1H), 3.99-3.93 (m, 1H), 3.43-3.38 (m, 1H),3.17-2.87 (m, 8H), 2.74 (s, 3H), 2.46-2.23 (m, 6H), 1.93-1.75 (m, 2H),1.70-1.60 (m, 1H); MS (ESI) m/z 546.0 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.22 (s, 1H), 4.49-4.37 (m, 2H), 4.13 (s, 1H),4.08-3.98 (m, 1H), 3.41 (dd, J=16.0 Hz and 4.0 Hz, 1H), 3.25-2.95 (m,10H), 2.47-2.12 (m, 6H), 1.90-1.75 (m, 2H), 1.70-1.60 (m, 1H), 1.38 (t,J=6.8 Hz, 3H); MS (ESI) m/z 560.0 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.26 (s, 1H), 4.68-4.61 (M, 1H), 4.44-4.39 (m,1H), 4.14 (s, 1H), 3.44-3.35 (m, 2H), 3.18-2.88 (m, 11H), 2.46-2.39 (m,1H), 2.30-2.26 (m, 1H), 2.15-1.60 (m, 8H), 0.89 (t, J=6.8 Hz, 3H); MS(ESI) m/z 588.1 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.22 (s, 1H), 4.64 (t, J=13.6 Hz, 1H), 4.38(t, J=12.8 Hz, 1H), 4.14 (s, 1H), 3.45-3.36 (m, 2H), 3.18-2.95 (m, 9H),2.86 (s, 3H), 2.46-2.38 (m, 1H), 2.29-2.26 (m, 1H), 1.70-1.60 (m, 1H),1.45 (t, J=6.8 Hz, 3H); MS (ESI) m/z 520.0 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.21 (s, 1H), 4.55-4.48 (m, 2H), 4.13 (s, 1H),3.44-3.39 (m, 1H), 3.18-2.86 (m, 12H), 2.46-2.39 (m, 1H), 2.28-2.25 (m,1H), 1.70-1.60 (m, 1H), 1.44-1.37 (m, 6H); MS (ESI) m/z 534.0 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.21 (s, 1H), 4.81-4.74 (m, 1H), 4.44-4.39 (m,1H), 4.13 (s, 1H), 3.84 (br s, 2H), 3.76-3.68 (m, 1H), 3.49 (br s, 2H),3.41 (dd, J=16.4 Hz and 4.4 Hz, 1H), 3.18-2.85 (m, 11H), 2.46-2.39 (m,1H), 2.29-2.26 (m, 1H), 1.70-1.60 (m, 1H), 1.22-1.18 (m, 6H); MS (ESI)m/z 578.0 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.23 (s, 1H), 4.72-4.66 (m, 1H), 4.57-4.52 (m,1H), 4.11 (s, 1H), 3.83-3.81 (m, 2H), 3.72-3.66 (m, 1H), 3.53-3.47 (m,1H), 3.45-3.34 (m, 4H), 3.17-2.95 (m, 9H), 2.47-2.39 (m, 1H), 2.28-2.24(m, 1H), 1.70-1.60 (m, 1H), 1.50 (t, J=6.8 Hz, 3H), 1.21-1.13 (m, 6); MS(ESI) m/z 592.0 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.23 (s, 1H), 4.80-4.70 (m, 2H), 4.13 (s, 1H),3.41 (dd, J=16.0 Hz and 4.4 Hz, 1H), 3.18-2.96 (m, 12H), 2.46-2.39 (m,1H), 2.29-2.25 (m, 1H), 1.70-1.60 (m, 1H), 1.10-0.82 (m, 4H); MS (ESI)m/z 532.0 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.24 (s, 1H), 4.76-4.60 (m, 2H), 4.13 (s, 1H),3.49-3.39 (m, 3H), 3.18-2.95 (m, 9H), 2.47-2.39 (m, 1H), 2.28-2.25 (m,1H), 1.70-1.61 (m, 1H), 1.49 (t, J=7.6 Hz, 3H), 1.10-0.80 (m, 3H),0.75-0.60 (m, 1H); MS (ESI) m 546.0 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.22 (s, 1H), 4.82-4.76 (m, 1H), 4.33-4.27 (m,1H), 4.13 (s, 1H), 3.75-3.65 (m, 1H), 3.47-3.39 (m, 1H), 3.18-2.75 (m,11H), 2.51-2.39 (m, 1H), 2.29-2.25 (m, 1H), 2.20-1.76 (m, 4H), 1.70-1.40(m, 4H), 1.30 (s, 3H), 0.99-0.96 (m, 6H); MS (ESI) m/z 628.1 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.25 and 7.24 (each s, total 1H), 4.82-4.73(m, 1H), 4.53-4.44 (m, 1H), 4.13 (s, 1H), 3.88-3.71 (m, 1H), 3.48-3.32(m, 3H), 3.18-2.95 (m, 8H), 2.54-2.36 (m, 2H), 2.29-2.25 (m, 1H),1.98-1.85 (m, 2H), 1.84-1.75 (m, 1H), 1.70-1.60 (m, 1H), 1.59-1.40 (m,3H), 1.38-1.27 (m, 6H), 1.00-0.93 (m, 6H); MS (ESI) m/z 642.1 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.29 (s, 1H), 4.97-4.94 (m, 1H), 4.68-4.65 (m,1H), 4.17-4.06 (m, 3H), 3.45-3.40 (m, 2H), 3.18-2.95 (m, 11H), 2.45-2.38(m, 1H), 2.30-2.26 (m, 1H), 1.70-1.61 (m, 1H), 1.05 (s, 9H); MS (ESI)m/z 592.1 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.26 (s, 1H), 4.75-4.67 (m, 2H), 4.12 (s, 1H),3.88-3.76 (m, 2H), 3.75-3.56 (m, 2H), 3.55-3.37 (m, 2H), 3.28-2.95 (m,10H), 2.46-2.39 (m, 1H), 2.29-2.25 (m, 1H), 1.71-1.61 (m, 1H), 1.30-1.10(m, 7H), 0.85-0.74 (m, 2H), 0.51-0.42 (m, 2H); MS (ESI) m/z 618.1 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.24 (s, 1H), 4.70-4.59 (m, 2H), 4.12 (s, 1H),3.42 (dd, J=16.4 Hz and 4.4 Hz, 1H), 3.25-2.95 (m, 12H), 2.47-2.40 (m,1H), 2.29-2.25 (m, 1H), 1.92-1.60 (m, 7H), 1.40-1.12 (m, 4H), 1.10-0.90(m, 2H), 0.89-0.78 (m, 2H), 0.52-0.45 (m, 2H); MS (ESI) m/z 628.1 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.26 (s, 1H), 4.75-4.60 (m, 2H), 4.13 (s, 1H),3.97-3.70 (m, 2H), 3.69-3.61 (m, 1H), 3.55-3.38 (m, 3H), 3.28-2.95 (m,11H), 2.86-2.76 (m, 1H), 2.48-2.40 (m, 1H), 2.31-2.19 (m, 2H), 1.76-1.57(m, 2H), 1.30-1.20 (m, 1H), 0.84-0.82 (m, 2H), 0.50-0.49 (m, 2H); MS(ESI) m/z 616.1 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.23 (s, 1H), 4.72-4.66 (m, 1H), 4.58-4.55 (m,1H), 4.13 (s, 1H), 3.42 (dd, J=16.0 Hz and 4.4 Hz, 1H), 3.28-2.95 (m,12H), 2.48-2.40 (m, 1H), 2.30-2.25 (m, 1H), 1.78-1.60 (m, 4H), 1.25-1.16(m, 1H), 0.98-0.95 (m, 6H) 0.83-0.79 (m, 2H) 0.48-0.46 (m, 2H): M (ESI)m/z 602.1 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.23 (s, 1H), 4.75-4.66 (m, 1H), 4.60-4.52 (m,1H), 4.12 (s, 1H), 3.47-3.38 (m, 1H), 3.25-2.95 (m, 12H), 2.48-2.40 (m,1H), 2.30-2.25 (m, 1H), 1.78-1.61 (m, 3H), 1.25-1.16 (m, 1H), 0.94 (s,9H), 0.83-0.80 (m, 2H), 0.49-0.47 (m, 2H); MS (ESI) m/z 616.0 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.24 (s, 1H), 4.74-4.61 (m, 2H), 4.13 (s, 1H),3.44-3.40 (m, 2H), 3.28-2.95 (m, 11H), 2.47-2.35 (m, 2H), 2.29-2.26 (m,1H), 2.00-1.90 (m, 1H), 1.75-1.59 (m, 5H), 1.38-1.16 (m, 3H), 0.85-0.78(m, 2H), 0.51-0.46 (m, 2H); MS (ESI) m/z 614.1 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.16 (s, 1H), 4.73 (br s, 1H), 4.48 (dd,J=27.6 Hz and 16.0 Hz, 2H), 4.10 (br s, 1H), 3.69-3.46 (m, 2H),3.40-3.29 (m, 1H), 3.10-2.88 (m, 7H), 2.38-2.20 (m, 2H), 1.98-1.72 (m,5H), 1.71-1.50 (m, 2H), 1.40-1.18 (m, 6H); MS (ESI) m/z 574.1 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.13 (s, 1H), 4.38 (s, 2H), 4.11 (s, 1H), 3.41(dd, J=16.0 Hz and 4.4 Hz, 1H), 3.22-2.87 (m, 10H), 2.45-2.37 (m, 1H),2.28-2.25 (m, 1H), 1.73-1.64 (m, 4H), 1.01-0.97 (m, 6H); MS (ESI) m/z548.0 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.25 (s, 1H), 4.62 (dd, J=18.4 Hz and 13.6 Hz,2H), 4.11 (s, 1H), 3.86-3.81 (m, 2H), 3.42 (dd, J=16.0 Hz and 4.8 Hz,1H), 3.18-2.95 (m, 8H), 2.49-2.41 (m, 1H), 2.37-2.24 (m, 3H), 1.83-1.76(m, 2H), 1.72-1.62 (m, 1H), 1.37-1.33 (m, 6H); MS (ESI) m/z 560.0 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.20 (s, 1H), 4.61 (t, J=12.8 Hz, 1H), 4.33(t, J=12.8 Hz, 1H), 4.13 (s, 1H), 3.41 (dd, J=16.4 Hz and 4.4 Hz, 1H),3.36-3.30 (m, 1H), 3.18-2.80 (m, 12H), 2.46-2.38 (m, 1H), 2.29-1.18 (m,3H), 2.10-2.00 (m, 1), 2.00-1.85 (m, 4H), 1.70-1.60 (m, 1H); MS (ESI)m/z 560.2 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.19 (s, 1H), 4.52-4.42 (m, 2H), 4.12 (s, 1H),3.45-3.38 (m, 1H), 3.28-2.80 (m, 12H), 2.49-2.40 (m, 1H), 2.30-2.13 (m,3H), 2.08-1.97 (m, 1H), 1.96-1.80 (m, 4H), 1.70-1.60 (m, 1H), 1.38 (t,J=7.2 Hz, 3H); MS (ESI) m/z 574.2 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.23 and 7.20 (each s, total 1H), 4.68-4.42(m, 2H), 4.13 (s, 1H), 3.85-3.75 (m, 1H), 3.47-3.38 (m, 1H), 3.18-2.85(m, 10H), 2.46-2.01 (m, 3H), 1.73-1.49 (m, 10H); MS (ESI) m/z 600.1(M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.25 (s, 1H), 4.70 (d, J=13.2 Hz, 1H), 4.42(d, J=13.2 Hz, 1H), 4.06 (s, 1H), 3.40 (dd, J=16.4 Hz and 4.8 Hz, 1H),3.12-2.80 (m, 12H), 2.44-2.36 (m, 1H), 2.23-2.20 (m, 1H), 1.67-1.57 (m,1H), 0.97 (s, 9H); MS (ESI) m/z 576.0 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.16 (s, 1H), 4.40 (s, 2H), 4.12-4.05 (m, 4H),3.90-3.84 (m, 1H), 3.78-3.71 (m, 1H), 3.44-3.37 (m, 1H), 3.15-2.95 (m,8H), 2.50-2.40 (m, 2H), 2.28-2.23 (m, 1H), 2.20-2.09 (m, 1H), 1.71-1.60(m, 1H); MS (ESI) m/z 548.1 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.16 (s, 1H), 4.32 (t, J=15.6 Hz, 1H), 4.17(t, J=15.6 Hz, 1H), 4.11 (s, 1H), 3.90-3.80 (m, 1H), 3.40 (dd, J=16.0 Hzand 4.4 Hz, 1H), 3.29-3.20 (m, 1H), 3.10-2.95 (m, 8H), 2.83-2.74 (m,1H), 2.41-2.20 (m, 3H), 2.12-1.90 (m, 3H), 1.70-1.60 (m, 1H); MS (ESI)m/z 599.9 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.21 (s, 1H), 4.66 (t, J=12.8 Hz, 1H), 4.37(t, J=12.8 Hz, 1H), 4.13 (s, 1H), 3.43-3.39 (m, 1H), 3.20-2.95 (m, 9H),2.86 (s, 3H), 2.46-2.39 (m, 1H), 2.28-2.25 (m, 1H), 1.80-1.60 (m, 8H),1.44-1.12 (m, 4H), 1.08-0.96 (m, 2H); MS (ESI) m/z 602.1 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.26 (s, 1H), 4.53 (s, 2H), 4.11 (s, 1H),3.71-3.62 (m, 2H), 3.40 (dd, J=16.4 Hz and 4.8 Hz, 1H), 3.16-2.95 (m,10H), 2.70-2.60 (m, 1H), 2.45-2.38 (m, 1H), 2.27-2.23 (m, 1H), 2.17-2.14(m, 2H), 1.96-1.83 (m, 2H), 1.70-1.59 (m, 1H); MS (ESI) m/z 614.1 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.19 (s, 1H), 4.82-4.77 (m, 1H), 4.39-4.36 (m,1H), 4.10 (s, 1H), 3.92-3.85 (m, 1H), 3.76-3.72 (m, 1H), 3.68-3.60 (m,1H), 3.51-3.32 (m, 5H), 3.17-2.95 (m, 9H), 2.45-2.37 (m, 1), 2.24-2.31(m, 2H), 2.20-2.10 (m, 1H), 2.05-1.87 (m, 2H), 1.70-1.59 (m, 1H); MS(ESI) m/z 576.1 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.10 (s, 1H), 4.36 (s, 2H), 4.11 (s, 1H), 3.40(dd, J=16.0 Hz and 4.4 Hz, 1H), 3.16-2.95 (m, 8H), 2.81 (s, 3H),2.45-2.37 (m, 1H), 2.27-2.24 (m, 1H), 1.70-1.60 (m, 1H); MS (ESI m/z492.1 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.21 (s, 1H), 4.50 (d, J=13.7 Hz, 1H), 4.43(d, J=13.7 Hz, 1H), 4.12 (s, 1H), 3.48-3.38 (m, 1H), 3.05 (s, 3H), 2.97(s, 3H), 3.16-2.94 (comp, 3H), 2.49-2.39 (m, 1H), 2.30-2.23 (m, 1H),1.72-1.61 (m, 1H), 1.40 (d, J=7.3 Hz, 3H), 1.05 (s, 9H); MS (ESI) m/z562.22 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.16 (s, 1H), 4.52 (d, J=13.4 Hz, 1H), 4.39(d, J=13.4 Hz, 1H), 4.11 (s, 1H), 3.49-3.36 (m, 1H), 3.05 (s, 3H), 2.96(s, 3H), 3.14-2.94 (comp, 3H), 2.48-2.38 (m, 1H), 2.29-2.22 (m, 1H),1.73-1.62 (m, 1H), 1.50 (d, J=6.7 Hz, 3H), 1.12-1.03 (m, 1H), 0.87-0.73(m, 2H), 0.67-0.59 (m, 1H), 0.44-0.36 (m, 1H); MS (ESI) m/z 546.16(M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.22 (s, 1H), 4.49 (s, 2H), 4.11 (s, 1H),3.60-3.37 (comp, 4H), 3.05 (s, 3H), 2.97 (s, 3H), 3.23-2.94 (comp, 3H),2.48-2.39 (m, 1H), 2.28-2.21 (m, 1H), 1.97-1.88 (m, 2H), 1.80-1.61 (m,2H), 1.53-1.38 (m, 2H), 1.01 (d, J=6.1 Hz, 3H); MS (ESI) m/z 560.19(M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.31 (s, 1H), 4.71 (d, J=13.4 Hz, 1H), 4.47(d, J=13.4 Hz, 1H), 4.11 (s, 1H), 3.48-3.38 (m, 1H), 3.04 (s, 3H), 2.96(s, 3H), 2.90 (s, 3H), 3.16-2.86 (comp, 3H), 2.50-2.40 (m, 1H),2.29-2.22 (m, 1H), 1.72-1.60 (m, 1H), 1.43 (d, J=6.7 Hz, 3H), 1.02 (s,9H); MS (ESI) m/z 576.20 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.19 (s, 1H), 4.57 (s, 2H), 4.11 (s, 1H),3.85-3.76 (m, 2H), 3.57-3.38 (m, 1H), 3.05 (s, 3H), 2.97 (s, 3H),3.15-2.81 (comp, 4H), 2.49-2.39 (m, 1H), 2.29-2.21 (m, 1H), 1.95-1.47(comp, 9H); MS (ESI) m/z 572.14 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.21-7.18 (m, 1H), 4.54-4.24 (m, 2H), 4.10 (s,1H), 3.49-3.35 (comp, 3H), 3.04 (s, 3H), 2.96 (s, 3H), 3.14-2.93 (comp,3H), 2.49-2.38 (m, 1H), 2.28-2.21 (m, 1H), 2.07-2.00 (m, 1H), 1.91-1.49(comp, 9H); MS (ESI) m/z 560.15 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.24 (s, 1H), 4.50 (d, J=13.7 Hz, 1H), 4.46(d, J=13.7 Hz, 1H), 4.12 (s, 1H), 3.57-3.36 (comp, 3H), 3.05 (s, 3H),2.96 (s, 3H), 3.20-2.94 (comp, 4H), 2.47-2.37 (m, 1H), 2.30-2.21 (m,1H), 1.99-1.47 (comp, 7H), MS (ESI) m/z 546.10 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.20 (s, 1H), 4.58 (s, 2H), 4.11 (s, 1H),3.69-3.56 (m, 2H), 3.48-3.36 (m, 2H), 3.04 (s, 3H), 2.96 (s, 3H),3.16-2.93 (comp, 3H), 2.46-2.37 (m, 1H), 2.29-1.98 (comp, 5H), 1.71-1.59(m, 1H); MS (ESI) m/z 532.09 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.24 (s, 1H), 4.53 (s, 2H), 4.11 (s, 1H),3.54-3.33 (comp, 5H), 3.04 (s, 3H), 2.96 (s, 3H), 3.14-2.93 (comp, 2H),2.47-2.38 (m, 1H), 2.28-2.21 (m, 1H), 2.06-1.60 (comp, 9H); MS (ESI) m/z560.15 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.25-7.23 (m, 1H), 4.53-4.47 (m, 2H), 4.12 (s,1H), 3.63-3.34 (comp, 8H), 3.04 (s, 3H), 2.96 (s, 3H), 3.14-2.94 (comp,3H), 2.47-2.37 (m, 1H), 2.31-1.60 (comp, 6H); MS (ESI) m/z 576.15 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.34-7.24 (comp, 4H), 7.21-7.17 (m, 1H), 4.69(s, 2H), 4.54 (s, 2H), 4.11 (s, 1H), 3.90-3.53 (m, 2H), 3.47-3.39 (m,2H), 3.04 (s, 3H), 2.96 (s, 3H), 3.28-2.94 (comp, 3H), 2.50-2.40 (m,1H), 2.29-2.22 (m, 1H), 1.72-1.61 (m, 1H); MS (ESI) m/z 594.15 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.32-7.26 (m, 2H), 6.99-6.94 (m, 2H),4.93-4.64 (comp, 6H), 4.13 (s, 1H), 3.81 (s, 3H), 3.46-3.33 (m, 1H),3.05 (s, 3H), 2.97 (s, 3H), 3.18-2.95 (comp, 2H), 2.50-2.39 (m, 1H),2.30-2.23 (m, 1H), 1.73-1.61 (m, 1H); MS (ESI) m/z 610.15 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.25 (s, 1H), 4.44 (s, 2H), 4.10 (s, 1H), 3.71(s, 4H), 3.47 (s, 4H), 3.44-3.33 (m, 1H), 3.04 (s, 3H), 2.95 (s, 3H),3.15-2.93 (comp, 2H), 2.45-2.36 (m, 1H), 2.27-2.20 (m, 1H), 1.71-1.59(m, 1H); MS (ESI) m/z 596.08 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.25 (s, 1H), 4.55 (d, J=13.7 Hz, 1H), 4.51(d, J=13.7 Hz, 1H), 4.12 (s, 1H), 3.56-3.31 (comp, 5H), 3.05 (s, 3H),2.96 (s, 3H), 3.16-2.94 (comp, 2H), 2.48-2.36 (m, 1H), 2.30-2.22 (m,1H), 2.14-1.59 (comp, 11H); MS (ESI) m: 574.18 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.22 (s, 1H), 4.81 (d, J=13.4 Hz, 1H), 4.31(d, J=13.4 Hz, 1H), 4.12 (s, 1H), 3.75-3.33 (comp, 4H), 3.06 (s, 3H),2.97 (s, 3H), 3.18-2.94 (comp, 2H), 2.50-1.61 (comp, 7H), 1.53 (d, J=6.1Hz, 3H); MS (ESI) m/z 546.20 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.23 (s, 1H), 4.77 (d, J=13.4 Hz, 1H), 4.33(d, J=13.4 Hz, 1H), 4.13 (s, 1H), 3.75-3.32 (comp, 4H), 3.05 (s, 3H),2.96 (s, 3H), 3.17-2.94 (comp, 2H), 2.46-1.97 (comp, 5H), 1.84-1.60(comp, 2H), 1.53 (d, J=6.1 Hz, 3H); MS (ESI) m/z 546.16 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.07 (s, 1H), 4.59 (s, 2H), 4.35-4.20 (m, 4H),4.11 (s, 1H), 3.43-3.37 (m, 1H), 3.05 (s, 3H), 2.97 (s, 3H), 3.15-2.95(comp, 2H), 2.67-2.20 (comp, 4H), 1.72-1.61 (m, 1H); MS (ESI) m/z 518.11(M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.24 (s, 1H), 5.58-5.39 (m, 1H), 4.68 (s, 2H),4.12 (s, 1H), 4.03-3.38 (comp, 5H), 3.05 (s, 3H), 2.97 (s, 3H),3.17-2.95 (comp, 2H), 2.83-2.20 (comp, 4H), 1.73-1.61 (m, 1H); MS (ESI)m/z 550.16 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.30-7.21 (m, 1H), 4.66-4.51 (m, 2H), 4.11 (s,1H), 3.84-3.31 (comp, 5H), 3.05 (s, 3H), 2.97 (s, 3H), 3.16-2.95 (comp,2H), 2.87-2.61 (m, 2H), 2.50-2.40 (m, 1H), 2.33-1.83 (comp, 5H),1.73-1.61 (m, 1H); MS (ESI) m/z 574.18 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.37 (s, 1H), 4.62 (d, J=14.0 Hz, 1H), 4.57(d, J=14.0 Hz, 1H), 4.12 (s, 1H), 3.75-3.66 (m, 2H), 3.48-3.32 (comp,3H), 3.04 (s, 3H), 2.96 (s, 3H), 3.17-2.94 (comp, 2H), 2.48-2.37 (m,1H), 2.29-2.22 (m, 1H), 2.22-2.13 (br, 2H), 1.98-1.60 (comp, 9H); MS(ESI) m/z 586.24 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.26-7.22 (m, 1H), 4.60-4.48 (m, 2H), 4.12 (s,1H), 4.12-4.01 (m, 1H), 3.73-3.33 (comp, 4H), 3.05 (s, 3H), 2.97 (s,3H), 3.29-2.95 (comp, 3H), 2.49-2.39 (m, 1H), 2.30-1.61 (comp, 8H); MS(ESI) m/z 576.22 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.31 (s, 1H), 7.23 (s, 4H), 4.62 (d, J=14.3Hz, 1H), 4.58 (d, J=14.3 Hz, 1H), 4.12 (s, 1H), 3.85-3.75 (m, 2H), 3.06(s, 3H), 2.97 (s, 3H), 3.63-2.94 (comp, 9H), 2.50-2.41 (m, 1H),2.30-2.23 (m, 1H), 1.73-1.62 (m, 1H); MS (ESI) m/z 608.21 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.23-7.15 (m, 1H), 4.74-4.61 (m, 1H),4.55-4.33 (m, 1H), 4.11 (s, 1H), 3.98-3.37 (comp, 3H), 3.04 (s, 3H),2.96 (s, 3H), 3.16-2.94 (comp, 3H), 2.50-2.37 (m, 1H), 2.30-2.21 (m,1H), 2.10-1.50 (comp, 12H); MS (ESI) m/z 574.32 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.24 (s, 1H), 4.64 (d, J=13.2 Hz, 1H), 4.58(d, J=13.2 Hz, 1H), 4.11 (s, 1H), 3.88-3.78 (m, 2H), 3.49-3.38 (m, 1H),3.04 (s, 3H), 2.96 (s, 3H), 3.16-2.93 (comp, 2H), 2.49-2.21 (comp, 4H),1.84-1.61 (m, 3H), 1.38-1.32 (m, 6H); MS (ESI) m/z 560.27 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.22 (s, 1H), 4.50 (d, J=13.7 Hz, 1H), 4.46(d, J=13.7 Hz, 1H), 4.14 (s, 1H), 3.48-3.36 (m, 1H), 3.06 (s, 3H), 2.97(s, 3H), 3.16-2.95 (comp, 3H), 2.48-2.37 (m, 1H), 2.32-2.23 (m, 1H),1.72-1.60 (m, 1H), 1.40 (d, J=6.7 Hz, 3H), 1.05 (s, 9H); MS (ESI) m/z562.23 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.23 (s, 1H), 4.42 (s, 2H), 4.14 (s, 1H), 3.31(br s, 1H), 3.39-3.45 (m, 1H), 2.97-3.14 (m, 8H), 2.26-2.44 (m, 3H),1.61-2.06 (m, 14H); MS (ESI) m/z 612.3 (M+H), calcd for C₃₂H₃₉ClN₃O₇612.24.

¹H NMR (400 MHz, CD₃OD) δ 7.27 (s, 1H), 4.71-4.87 (m, 2H), 4.14 (s, 1H),3.37-3.46 (m, 2H), 2.94-3.28 (m, 10H), 2.42 (dd, J=14.0, 14.0 Hz, 1H),2.24-2.32 (m, 1H), 1.60-1.70 (m, 1H), 1.27-1.36 (m, 1H), 0.51-1.14 (m,8H); MS (ESI) m/z 572.3 (M+H), calcd for C₂₉H₃₅ClN₃O₇ 572.21.

¹H NMR (400 MHz, CD₃OD) δ 7.24 (s, 1H), 4.60-5.00 (m, 4H), 4.14 (s, 1H),3.64-3.82 (m, 2H), 3.20-3.46 (m, 3H), 2.94-3.20 (m, 8H), 2.41 (dd,J=14.0, 14.0 Hz, 1H), 2.25-2.29 (m, 1H), 1.60-1.70 (m, 1H), 1.24-1.28(m, 1H), 0.78-0.86 (m, 2H), 0.46-0.52 (m, 2H); MS (ESI) m/z 578.3 (M+H),calcd for C₂₈H₃₄ClFN₃O₇ 578.20.

¹H NMR (400 MHz, CD₃OD) δ 7.23 (s, 1H), 4.63-5.00 (m, 4H), 4.13 (s, 1H),3.61-3.72 (m, 2H), 3.20-3.43 (m, 3H), 2.94-3.20 (m, 8H), 2.42 (dd,J=14.0, 14.0 Hz, 1H), 2.25-2.29 (m, 1H), 1.85-1.88 (m, 2H), 1.60-1.70(m, 1H), 1.01 (t, J=7.3 Hz, 3H); MS (ESI) m/z 566.3 (M+H), calcd forC₂₇H₃₄FN₃O₇ 566.20.

¹H NMR (400 MHz, CD₃OD) δ 7.22 (s, 1H), 4.72 (dd, J=13.7, 13.7 Hz, 1H),4.34 (dd, J=10.2, 10.2 Hz, 1H), 4.14 (s, 1H), 3.38-3.44 (m, 1H),2.87-3.21 (m, 13H), 2.42 (dd, J=14.0, 14.0 Hz, 1H), 2.23-2.31 (m, 2H),1.60-1.70 (m, 1H), 1.09 (d, J=6.5 Hz, 3H), 1.05 (d, J=6.5 Hz, 3H); MS(ESI) m/z 548.3 (M+H), calcd for C₂₇H₃₅ClFN₃O₇ 548.21.

¹H NMR (400 MHz, CD₃OD) δ 7.23 (s, 1H), 4.63 (dd, J=13.7, 13.7 Hz, 1H),4.47 (dd, J=10.2, 10.2 Hz, 1H), 4.14 (s, 1H), 3.29-3.44 (m, 3H),2.94-3.21 (m, 10H), 2.43 (dd, J=14.0, 14.0 Hz, 1H), 2.18-2.29 (m, 2H),1.60-1.70 (m, 1H), 1.40 (t, J=7.3 Hz, 3H), 1.09 (d, J=6.5 Hz, 3H), 1.03(d, J=6.5 Hz, 3H); MS (ESI) m/z 562.3 (M+H), calcd for C₂₈H₃₇ClN₃O₇562.22.

¹H NMR (400 MHz, CD₃OD) δ 7.20 (s, 1H), 4.75-4.80 (m, 1H), 4.33-4.37 (m,1H), 4.11 (s, 1H), 2.88-3.49 (m, 16H), 2.43 (dd, J=15.0, 15.0 Hz, 1H),2.23-2.26 (m, 1H), 1.60-1.70 (m, 1H), 1.19-1.28 (m, 1H), 0.80-0.82 (m,2H), 0.46-0.50 (m, 2H); MS (ESI) m/z 546.2 (M+H), calcd for C₂₇H₃₃ClN₃O₇546.19.

¹H NMR (400 MHz, CD₃OD) δ 7.20 (s, 1H), 4.72 (dd, J=12.8, 12.8 Hz, 1H),4.32 (dd, J=4.4, 12.8 Hz, 1H), 4.12 (s, 1H), 3.40 (dd, J=4.6, 16.0 Hz,1H), 2.87-3.14 (m, 13H), 2.43 (dd, J=15.0, 15.0 Hz, 1H), 2.24-2.28 (m,1H), 1.60-1.98 (m, 7H), 1.21-1.42 (m, 3H), 1.01-1.12 (m, 2H); MS (ESI)m/z 588.3 (M+H), calcd for C₃₀H₃₉ClN₃O₇ 588.24.

¹H NMR (400 MHz, CD₃OD) δ 7.20 (s, 1H), 4.83-4.95 (m, 1H), 4.14-4.19 (m,1H), 4.10 (s, 1H), 2.74-3.50 (m, 12H), 2.42 (dd, J=15.0, 15.0 Hz, 1H),2.22-2.28 (m, 1H), 1.90-2.20 (m, 2H), 1.60-1.70 (m, 1H), 1.53 (s, 3H),1.50 (s, 3H), 1.08 (t, J=7.3 Hz, 3H); MS (ESI) m/z 562.3 (M+H), calcdfor C₂₈H₃₇ClN₃O₇ 562.22.

¹H NMR (400 MHz, CD₃OD) δ 7.22 (s, 1H), 4.91-4.99 (m, 1H), 4.18-4.22 (m,1H), 4.12 (s, 1H), 3.41 (dd, J=4.6, 16.0 Hz, 1H), 2.96-3.10 (m, 11H),2.45 (dd, J=15.0, 15.0 Hz, 1H), 2.24-2.30 (m, 1H), 1.61-1.71 (m, 1H),1.42 (s, 6H), 1.28-1.36 (m, 1H), 0.76-0.81 (m, 2H), 0.64-0.72 (m, 2H);MS (ESI) m/z 574.2 (M+H), calcd for C₂₉H₃₇ClN₃O₇ 574.22.

¹H NMR (400 MHz, CD₃OD) δ 7.23 (s, 1H), 4.46-4.63 (m, 2H), 4.14 (s, 1H),3.95-4.02 (m, 1H), 3.40 (dd, J=4.6, 16.0 Hz, 1H), 2.96-3.21 (m, 10H),2.41 (dd, J=15.0, 15.0 Hz, 1H), 2.26-2.29 (m, 1H), 1.60-1.70 (m, 1H),1.50 (d, J=6.4 Hz, 3H), 1.41 (d, J=6.4 Hz, 3H), 1.06-1.17 (m, 1H),0.72-0.78 (m, 2H), 0.42-0.44 (m, 2H); MS (ESI) m/z 574.2 (M+H), calcdfor C₂₉H₃₇ClN₃O₇ 574.22.

¹H NMR (400 MHz, CD₃OD) δ 7.30 (s, 1H), 4.50-4.60 (m, 2H), 4.14 (s, 1H),3.78-3.84 (m, 1H), 3.42 (dd, J=4.6, 16.0 Hz, 1H), 2.94-3.21 (m, 10H),2.42 (dd, J=15.0, 15.0 Hz, 1H), 2.26-2.30 (m, 1H), 1.96-2.02 (m, 1H),1.60-1.70 (m, 1H), 1.50 (d, J=6.4 Hz, 3H), 1.44 (d, J=6.4 Hz, 3H), 1.03(d, J=6.4 Hz, 3H), 0.94 (d, J=6.4 Hz, 3H); MS (ESI) m/z 576.3 (M+H),calcd for C₂₉H₃₉ClN₃O₇ 576.24.

¹H NMR (400 MHz, CD₃OD) δ 7.24 (s, 1H), 4.63 (dd, J=14.2, 14.2 Hz, 1H),4.40 (dd, J=14.2, 14.2 Hz, 1H), 4.14 (s, 1H), 3.78-3.84 (m, 1H), 3.42(dd, J=4.6, 16.0 Hz, 1H), 2.96-3.28 (m, 10H), 2.42 (dd, J=15.0, 15.0 Hz,1H), 2.26-2.29 (m, 1H), 1.54-1.70 (m, 4H), 1.51 (d, J=6.4 Hz, 3H), 1.43(d, J=6.4 Hz, 3H), 0.89-0.94 (m, 6H); MS (ESI) m/z 590.3 (M+H), calcdfor C₃₀H₄₁ClN₃O₇ 590.26.

¹H NMR (400 MHz, CD₃OD) δ 7.22 (s, 1H), 4.74 (dd, J=14.2, 14.2 Hz, 1H),4.34 (dd, J=8.7, 14.2 Hz, 1H), 4.13 (s, 1H), 3.41 (dd, J=4.6, 16.0 Hz,1H), 2.88-3.34 (m, 13H), 2.39-2.46 (m, 2H), 2.26-2.28 (m, 1H), 1.96-2.01(m, 2H), 1.61-1.74 (m, 5H), 1.23-1.35 (m, 2H); MS (ESI) m/z 574.2 (M+H),calcd for C₂₉H₃₇ClN₃O₇ 574.22.

¹H NMR (400 MHz, CD₃OD) δ 7.22 (s, 1H), 4.62 (dd, J=14.2, 14.2 Hz, 1H),4.48 (dd, J=8.7, 14.2 Hz, 1H), 4.14 (s, 1H), 3.41 (dd, J=4.6, 16.0 Hz,1H), 2.96-3.34 (m, 12H), 2.26-2.41 (m, 3H), 1.96-2.01 (m, 2H), 1.61-1.74(m, 5H), 1.40 (t, J=7.3 Hz, 3H), 1.22-1.32 (m, 2H); MS (ESI) m/z 588.3(M+H), calcd for C₃₀H₃₇ClN₃O₇ 588.24.

¹H NMR (400 MHz, CD₃OD) δ 7.23 (s, 1H), 4.75 (dd, J=9.6, 12.8 Hz, 1H),4.28 (dd, J=9.6, 12.8 Hz, 1H), 4.12 (s, 1H), 3.92 (d, J=12.1 Hz, 1H),3.71 (d, J=12.1 Hz, 1H), 3.38-3.47 (m, 1H), 2.97-3.16 (m, 8H), 2.72 (s,3H), 2.38-2.47 (m, 1H), 2.25-2.28 (m, 1H), 1.60-1.70 (m, 1H), 1.51 (s,3H), 1.46 (s, 3H); MS (ESI) m/z 564.3 (M+H), calcd for C₂₇H₃₅ClN₃O₈564.20.

¹H NMR (400 MHz, CD₃OD) δ 7.21-7.16 (m, 1H), 4.78-4.49 (m, 2H), 4.12 (s,1H), 3.71-3.32 (comp, 3H), 3.16-2.95 (comp, 2H), 3.04 (s, 3H), 2.96 (s,3H), 2.46-2.36 (m, 1H), 2.30-2.22 (m, 1H), 2.14-1.58 (comp, 7H),1.45-1.26 (comp, 6H); MS (ESI) m/z 574.18 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.23 (s, 1H), 4.44 (s, 2H), 4.23 (s, 2H), 4.10(s, 1H), 3.48-3.36 (comp, 1H), 3.04 (s, 3H), 2.96 (s, 3H), 3.14-2.94(comp, 2H), 2.49-2.02 (comp, 6H), 1.98-1.81 (m, 4H), 1.72-1.61 (m, 1H);MS (ESI) m/z 558.21 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.28 (s, 1H), 4.68-4.48 (m, 2H), 4.13 (s, 1H),4.12-4.02 (m, 1H), 3.90-3.80 (m, 1H), 3.49-3.38 (m, 1H), 3.05 (s, 3H),2.97 (s, 3H), 3.17-2.95 (comp, 2H), 2.52-2.23 (comp, 4H), 1.98-1.60(comp, 3H), 1.48-1.34 (m, 6H); MS ESI m/z 560.28 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.26 (s, 1H), 4.52 (s, 2H), 4.11 (s, 1H),4.10-4.00 (m, 1H), 3.90-3.80 (m, 1H), 3.46-3.37 (m, 1H), 3.05 (s, 3H),2.96 (s, 3H), 3.16-2.90 (comp, 2H), 2.52-2.12 (m, 4H), 1.98-1.58 (m,3H), 1.48-1.33 (comp, 6H); MS (ESI) m/z 560.27 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.25 (s, 1H), 4.68 (d, J=14.4 Hz, 1H), 4.51(d, J=14.4 Hz, 1H), 4.11 (s, 1H), 3.88-3.66 (m, 2H), 3.45-3.37 (m, 1H),3.04 (s, 3H), 2.96 (s, 3H), 3.15-2.94 (comp, 2H), 2.49-2.38 (m, 1H),2.29-2.21 (m, 1H), 2.19-2.08 (m, 1H), 1.95-1.59 (comp, 6H), 1.48 (d,J=6.7 Hz, 3H), 1.44 (d, J=6.7 Hz, 3H); MS (ESI) m/z 574.30 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.23 (s, 1H), 5.58-5.38 (m, 1H), 4.67 (s, 2H),4.11 (s, 1H), 4.03-3.30 (comp, 5H), 3.04 (s, 3H), 2.96 (s, 3H),3.22-2.94 (comp, 2H), 2.76-2.10 (comp, 4H), 1.72-1.59 (m, 1H); MS (ESI)m/z 550.18 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 6.99 (s, 1H), 6.94 (s, 1H), 4.14 (s, 2H), 4.11(s, 1H), 3.16-2.90 (m, 9H), 2.62-2.55 (m, 1H), 2.25-2.20 (m, 1H),1.65-1.56 (m, 1H), 1.46 (s, 9H); MS (ESI) m/z 500.1 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 6.92 (s, 1H), 6.86 (s, 1H), 4.18 (dd, J=43.6Hz and 13.2 Hz, 2H), 4.04 (s, 1H), 2.97-2.83 (m, 10H), 2.56-2.46 (m,1H), 2.18-1.14 (m, 1H), 1.57-1.47 (m, 1H), 1.39-1.38 (m, 3H), 0.99-0.97(m, 1H), 0.72-0.64 (m, 2H), 0.51-0.49 (m, 1H), 0.28-0.26 (m, 1H); MS(ESI) m/z 512.0 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 6.97 (s, 1H), 6.91 (s, 1H), 4.15 (s, 2H), 4.10(s, 1H), 3.15-2.87 (m, 11H), 2.67-2.52 (m, 2H), 2.24-2.16 (m, 1H),1.98-1.88 (m, 2H), 1.81-1.43 (m, 9H), 1.34-1.20 (m, 2H); MS (ESI) m/z554.0 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 6.99 (s, 1H), 6.94 (s, 1H), 4.33 (s, 2H), 4.09(s, 1H), 3.57-3.47 (m, 2H), 3.03 (s, 3H), 2.96 (s, 3H), 3.23-2.87 (comp,5H), 2.64-2.55 (m, 1H), 2.24-1.94 (comp, 5H), 1.66-1.54 (comp, 1H); MS(ESI) m/z 498.19

To a suspension of

Boc-amino)isobutyric acid (3.0 g, 14.8 mmol, 1.0 equiv) in 4:1dichloromethane-dimethylformamide (30 mL) was added hydoxybenzotriazole(2.19 g, 16.2 mmol, 1.1 equiv) and dicyclohexycarbodiimide (3.26 g, 15.8mmol, 1.07 equiv). After stirring at rt for 30 min, solution ofdimethylamine in THF (2.0 M, 11 mL, 22.1 mmol, 1.5 equiv) was added. Thereaction mixture was stirred at rt for another 16 h and then dilutedwith dichloromethane (100 mL). The reaction solution was washedsequentially with saturated NaHCO₃ (2×30 mL), H₂O (30 mL), citric acid(10% w/v, 2×30 mL), and brine (30 mL). The organic solution was driedover sodium sulfate, and concentrated to give the crude product, whichwas purified by Biotage to provide the desired dimethylamide as whitesolid.

The dimethylamide prepared above was dissolved in a solution of HCl indioxane (4.0 M, 25 mL). The reaction mixture was stirred at rt for anovernight. After evaporating volatiles, the white solid residue waswashed with diethylether, and further dried under high vacuum. Theformed amine hydrochloric acid salt was used directly for the next step.

To a solution of compound S15-8 (0.10 g, 0.26 mmol, 1.0 equiv) in1,2-dichloroethane (10 mL) was added amine hydrochloric acid salt (0.131mg, 0.79 mmol, 3.0 equiv) and triethylamine (0.11 mL, 0.79 mmol, 3.0equiv). After stirring at rt for 30 min, acetic acid (0.045 mL, 0.79mmol, 3.0 equiv) was added. After another 24 hrs, sodiumtriacetoxyborohydride (0.111 g, 0.53 mmol, 2.0 equiv) was added.Stirring was continued for 36 hrs. The reaction mixture was poured intosaturated aqueous NaHCO₃ and extracted three times with dichloromethane.The combined organic extracts were washed with brine, dried over sodiumsulfate, and concentrated to give the crude intermediate as off-whiteoil. The crude intermediate was redissolved in 1,2-dichloroethane (2mL). Formaldehyde (37 wt % in H₂O, 0.044 mL, 0.59 mmol) and acetic acid(0.034 mL, 0.059 mmol) were added. After stirring at rt for 1 h, sodiumtriacetoxyborohydride (0.083 g, 0.39 mmol) was added. Stirring wascontinued for another hour. The reaction mixture was poured intosaturated aqueous NaHCO₃ and extracted three times with dichloromethane.The combined organic extracts were washed with brine, dried over sodiumsulfate, and concentrated. Purification of the residue by Biotage gavecompound S15-15-2 as a colorless oil: ¹H NMR (400 MHz, CDCl₃) δ7.20-7.44 (m, 8H), 7.12 (d, J=7.8 Hz, 2H), 6.98 (s, 1H), 5.14 (s, 2H),3.61 (s, 2H), 3.41 (s, 3H), 2.89 (s, 3H), 2.46 (s, 3H), 2.04 (s, 3H),1.38 (s, 6H); MS (ESI) m/z 509.2 (M+H), calcd for C₂₉H₃₄ClN₂O₄ 509.21.

Compound S15-13-227 was prepared from S15-15-2 using similar proceduresto that of S15-13-15. The crude product was purified by HPLC on a WatersAutopurification system using a Phenomenex Polymerx 10μ RP-γ 100 Rcolumn [30×21.20 mm, 10 micron; flow rate, 20 mL/min; Solvent A: 0.05 NHCl/water; Solvent B: MeOH; injection volume: 4.0 mL (0.05 N HCl/water);gradient: 10-100% B over 20 min; mass-directed fraction collection].Fractions containing the desired product, eluting at 11.30-14.05 min,were collected and freeze-dried to give the desired product S15-13-227as a yellow solid: ¹H NMR (400 MHz, CD₃OD) δ 7.61 and 7.59 (s, 1H), 4.36(br s, 2H), 4.13 (s, 1H), 3.42 (dd, J=4.6, 16.0 Hz, 1H), 2.97-3.16 (m,14H), 2.71 (s, 3H), 2.43 (dd, J=15.1 Hz, 1H), 2.25-2.28 (m, 1H), 1.89(s, 3H), 1.69 (s, 3H), 1.60-1.70 (m, 1H); MS (ESI) m/z 605.4 (M+H),calcd for C₂₉H₃₈ClN₄O₈ 605.23.

Compound S15-13-228 was prepared using similar procedures to that ofS15-13-227, a yellow solid: ¹H NMR (400 MHz, CD₃OD) δ 7.44 (s, 1H),4.31-4.45 (m, 2H), 4.13 (s, 1H), 3.42 (dd, J=4.6, 16.0 Hz, 1H),2.97-3.16 (m, 11H), 2.73 (s, 3H), 2.43 (dd, J=15.1 Hz, 1H), 2.25-2.28(m, 1H), 1.75 (s, 3H), 1.63 (s, 3H), 1.60-1.70 (m, 1H); MS (ESI) m/z591.5 (M+H), calcd for C₂₈H₃₆ClN₄O₈ 591.21.

Compound S15-13-229 was prepared using similar procedures to that ofS15-13-227, a yellow solid: ¹H NMR (400 MHz, CD₃OD) δ 7.46 (s, 1H),4.35-4.38 (m, 2H), 4.12 (s, 1H), 3.42 (dd, J=4.6, 16.0 Hz, 1H),2.97-3.16 (m, 8H), 2.73 (s, 3H), 2.43 (dd, J=15.1 Hz, 1H), 2.25-2.28 (m,1H), 1.78 (s, 3H), 1.66 (s, 3H), 1.60-1.70 (m, 1H); MS (ESI) m/z 577.5(M+H), calcd for C₂₇H₃₄ClN₄O₈ 577.20.

Compound S15-13-230 was prepared using similar procedures to that ofS15-13-227, a yellow solid: ¹H NMR (400 MHz, CD₃OD) δ 7.39 (s, 1H), 4.39(dd, J=9.6, 12.8 Hz, 1H), 4.23 (dd, J=9.6, 12.8 Hz, 1H), 4.13 (s, 1H),3.41 (dd, J=4.6, 16.0 Hz, 1H), 2.97-3.16 (m, 8H), 2.71 (s, 3H), 2.40(dd, J=15.1 Hz, 1H), 2.25-2.28 (m, 1H), 1.78 (s, 3H), 1.62 (s, 3H),1.60-1.70 (m, 1H), 1.44 (s, 9H); MS (ESI) m/z 633.6 (M+H), calcd forC₃₁H₄₂ClN₄O₈ 633.26.

Compound S15-13-231 was prepared using similar procedures to that ofS15-13-227, a yellow solid: ¹H NMR (400 MHz, CD₃OD) δ 7.67 (d, J=7.8 Hz,2H), 7.53 (s, 1H), 7.38 (t, J=7.8 Hz, 2H), 7.20 (d, J=7.8 Hz, 1H), 4.46(s, 2H), 4.13 (s, 1H), 3.42 (dd, J=4.6, 16.0 Hz, 1H), 2.97-3.16 (m, 8H),2.80 (s, 3H), 2.42 (dd, J=15.1 Hz, 1H), 2.25-2.28 (m, 1H), 1.94 (s, 3H),1.78 (s, 3H), 1.60-1.70 (m, 1H); MS (ESI) m/z 653.5 (M+H), calcd forC₃₃H₃₈ClN₄O₈ 653.23.

Example 16 Synthesis of Compounds Via Scheme 16

The following compounds were prepared according to Scheme 16.

A solution of HNO₃ (68-70%, 0.56 mL, 8.57 mmol, 1.05 equiv) inconcentrated H₂SO₄ (2 mL) was added dropwise to a solution of compoundS15-4-a (2.00 g, 8.16 mmol, 1.0 equiv) in concentrated H₂SO₄ (20 mL) at0° C. The reaction mixture was stirred at 0° C. for 10 min and pouredonto ice (˜200 mL). The mixture was extracted with EtOAc (150 mL). Theorganic phase was separated, washed with brine (2×50 mL), dried overmagnesium sulfate, filtered, and concentrated to give crude S16-1 as anorange solid: ¹H NMR (400 MHz, CDCl₃) δ 11.5 (br s, 1H), 7.06 (s, 1H),3.90 (s, 3H), 2.32 (s, 3H); MS (ESI) m/z 288.01, 289.99 (M−H).

Compound S16-1 was dissolved in dichloromethane (16 mL). Oxalyl chloride(0.85 mL, 9.79 mmol, 1.2 equiv) was added, followed by a few drops ofDMF. The reaction mixture was stirred at rt for 30 min, concentrated,and further dried under high vacuum. The residue was redissolved indichloromethane (16 mL). Phenol (0.92 g, 9.79 mmol, 1.2 equiv),triethylamine (2.84 mL, 20.40 mmol, 2.5 equiv), and DMAP (100 mg, 0.82mmol, 0.1 equiv) were added. The reaction was stirred at rt for 1 h andconcentrated under reduced pressure. The residue was dissolved in EtOAc(150 mL), washed with 1 N aqueous HCl (50 mL), brine (50 mL), 1 Naqueous NaOH (50 mL), and then brine (50 mL), dried over anhydrousmagnesium sulfate, filtered, and concentrated to afford the desiredproduct S16-2 as a light yellow solid: ¹H NMR (400 MHz, CDCl₃) δ7.45-7.41 (m, 2H), 7.30-7.26 (m, 1H), 7.21-7.16 (m, 2H), 7.09 (s, 1H),3.94 (s, 3H), 2.38 (s, 3H); MS (ESI) m/z 364.05, 366.06 (M−H).

A solution of BBr₃ in dichloromethane (1.0 M, 8.16 mL, 8.16 mmol, 1.0equiv) was added slowly to a solution of compound S16-2 indichloromethane (32 mL) at −78° C. The reaction was stirred at −78° C.for 15 min and then allowed to warm to 0° C. in 50 min and kept at thattemperature for 10 min. The reaction mixture was poured into saturatedaqueous NaHCO₃ solution (50 mL) and stirred at rt for 10 min. Thedichloromethane was evaporated. The residue was extracted with EtOAc(100 mL, then 30 mL). The organic extracts were combined and dried overanhydrous magnesium sulfate. The dried solution was filtered, and thefiltrate was concentrated to give crude S16-3 (2.20 g): ¹H NMR (400 MHz,CDCl₃) δ 11.2 (br s, 1H), 7.48-7.44 (m, 2H), 7.36-7.32 (m, 1H), 7.25 (s,1H), 7.18-7.16 (m, 2H), 2.63 (s, 3H); MS (ESI) m/z 350.01, 352.03 (M−H).

Benzylbromide (0.78 mL, 6.56 mmol, 1.05 equiv) and K₂CO₃ powder (1.73 g,12.50 mmol, 2.0 equiv) were added to a solution of compound S16-3 (2.20g, 6.25 mmol, 1.0 equiv) in acetone (12 mL). The mixture was stirred atrt overnight. The solid was filtered off and further washed with EtOAc(30 mL). The filtrate was concentrated. The residue was purified byflash column chromatography (2-20% EtOAc/hexanes) to afford the desiredproduct S16-4 as a white solid (1.68 g, 47% over four steps): ¹H NMR(400 MHz, CDCl₃) δ 7.40-7.32 (m, 8H), 7.15 (s, 1H), 7.03-7.01 (m, 2H),5.18 (s, 2H), 2.39 (s, 3H); MS (ESI) m/z 440.09, 442.06 (M−H).

Zn dust (2.33 g, 35.70 mmol, 10.0 equiv) was added portionwise to asolution of compound S16-4 (1.58 g, 3.57 mmol, 1.0 equiv) in a mixtureof THF (5 mL) and HOAc (1 mL) (caution: exothermic!). The reactionmixture was stirred at rt for 3.5 hrs, diluted with EtOAc, and filteredthrough a pad of Celite. The cake was washed thoroughly with EtOAc. Thefiltrate was washed with saturated aqueous NaHCO₃ (60 mL). The aqueouslayer was extracted with EtOAc (40 mL). The combined extracts were driedover sodium sulfate, filtered and concentrated to yield the crudeaniline intermediate S16-4a, which was used directly in the next step.

HCHO (1.59 mL, 37% aqueous solution, 21.42 mmol, 6.0 equiv), HOAc (0.62mL, 10.71 mmol, 3.0 equiv) and Na(OAc)₃BH (2.27 g, 10.71 mmol, 3.0equiv) were added to a solution of the above crude product S16-4a inacetonitrile (30 mL). The reaction mixture was then stirred at rt for 2h. Then Na(OAc)₃BH (0.38 g, 1.78 mmol, 0.5 equiv) was added. Thereaction mixture was stirred at rt overnight. Saturated aqueous NaHCO₃(70 mL) was added slowly (bubbling). The resulting mixture was thenstirred at rt for 5 min and extracted with EtOAc (100 mL, then 50 mL).The combined extracts were dried over sodium sulfate, filtered andconcentrated. The residue was purified by flash column chromatography(2-5% EtOAc/hexanes) to afford the desired product S16-5 as a whitesolid (1.43 g, 91% over 2 steps): ¹H NMR (400 MHz, CDCl₃) δ 7.44-7.35(m, 7H), 7.26-7.22 (m, 1H), 7.09-7.07 (m, 3H), 5.10 (s, 2H), 2.83 (s,6H), 2.42 (s, 3H); MS (ESI) m/z 440.12, 442.13 (M+H).

n-BuLi (1.46 mL, 2.17 M/hexanes, 3.16 mmol, 1.10 equiv) was addeddropwise to a solution of diisopropylamine (0.45 mL, 3.16 mmol, 1.10equiv) in THF (6 mL) at −78° C. The reaction solution was warmed to −20°C. and then re-cooled to −78° C. TMEDA (0.47 mL, 3.16 mmol, 1.10 equiv)was added and the reaction mixture was stirred at −78° C. for 15 min. Asolution of ester S16-5 (1.27 g, 2.88 mmol, 1.05 equiv) in THF (3 mL)was added via a cannula. The resulting deep red solution was stirred at−78° C. for 55 min and was then cooled to −100° C. A solution of enoneS1-9 (1.33 g, 2.75 mmol, 1.0 equiv) in THF (3 mL) was added to thereaction mixture via a cannula. The reaction mixture was allowed to warmto −70° C. over 30 min. LHMDS (3.02 mL, 1.0 M/THF, 3.02 mmol, 1.1 equiv)was added. The reaction mixture was warmed to −5° C. slowly over 1 h 20min, quenched by a mixture of saturated aqueous NH₄Cl and pH 7 phosphatebuffer (100 mL, 1:1, v/v), and extracted with EtOAc (75 mL, then 25 mL).The combined EtOAc extracts were dried (sodium sulfate), filtered andconcentrated. The residue was purified by a preparative reverse phaseHPLC on a Waters Autopurification system using a Sunfire Prep C18 OBDcolumn [5 μm, 19×50 mm; flow rate, 20 mL/min; Solvent A: H₂O with 0.1%HCO₂H; Solvent B: CH₃CN with 0.1% HCO₂H; injection volume: 4.0 mL(CH₃CN), gradient: 80→100% B in A over 10 min; mass-directed fractioncollection]. Fractions containing the desired product, eluting at 7.6-11min, were collected and concentrated at rt to remove most of theacetonitrile. The resulting mostly aqueous solution was freeze-dried toyield the desired product S16-6 (1.71 g, 75%): ¹H NMR (400 MHz, CDCl₃) δ16.00 (br s, 1H), 7.50-7.46 (m, 4H), 7.39-7.27 (m, 6H), 7.10 (s, 1H),5.36 (s, 2H), 5.18, 5.12 (ABq, J=12.8 Hz, 2H), 4.10 (d, J=10.4 Hz, 1H),3.37 (dd, J=4.3, 15.9 Hz, 1H), 2.88-2.74 (m, 7H), 2.55-2.40 (m, 9H),2.12 (d, J=14.0 Hz, 1H), 0.84 (s, 9H), 0.28 (s, 3H), 0.14 (s, 3H); MS(ESI) m/z 828.27, 830.30 (M+H).

A solution of phenyllithium in di-n-butyl ether (0.10 mL, 1.8 M, 0.18mmol, 1.5 equiv) was added dropwise to a solution of compound S16-6(0.10 g, 0.12 mmol, 1.0 equiv) in THF (3 mL) at −78° C., forming anorange solution. After 5 min, a solution of n-butyllithium in hexanes(68 μL, 2.2 M, 0.15 mmol, 1.2 equiv) was added dropwise at −78° C.,followed 2 min later by the addition of N,N-dimethylformamide (47 μL,0.61 mmol, 5.0 equiv). The resulting dark red reaction mixture wasstirred at −78° C. for 65 min. Saturated aqueous ammonium chloride (10mL) was added dropwise at −78° C. The reaction mixture was allowed towarm to 23° C., diluted with saturated aqueous ammonium chloride (−20mL), and extracted with EtOAc (2×15 mL). The organic extracts werecombined, dried over anhydrous sodium sulfate, filtered, andconcentrated, affording compound S16-7 as an orange oil, which was useddirectly in the next reactions: ¹H NMR (400 MHz, CDCl₃) δ 15.85 (s, 1H),10.32 (s, 1H), 7.50-7.46 (m, 4H), 7.39-7.26 (m, 7H), 5.36 (s, 2H), 5.25,5.18 (ABq, J=12.8 Hz, 2H), 4.02 (d, J=11.0 Hz, 1H), 3.13 (dd, J=4.9,15.9 Hz, 1H), 2.98-2.90 (m, 7H), 2.58-2.46 (m, 9H), 2.15 (d, J=14.0 Hz,1H), 0.83 (s, 9H), 0.27 (s, 3H), 0.15 (s, 3H); MS (ESI) m/z 778.34(M+H).

t-Butylamine (19 μL, 0.18 mmol, 3.0 equiv), acetic acid (10 μL, 0.18mmol, 3.0 equiv) and sodium triacetoxyborohydride (26 mg, 0.12 mmol, 2.0equiv) were added sequentially to a solution of compound S16-7 (half ofthe above crude product, 0.061 mmol, 1.0 equiv) in 1,2-dichloroethane (2mL) at 23° C. After stirring for 1 h 45 min, the reaction mixture wasquenched by the addition of saturated aqueous sodium bicarbonate andbrine (1:1, 15 mL) and extracted with dichloromethane (2×15 mL). Thecombined organic extracts were dried over anhydrous sodium sulfate,filtered, and concentrated. The residue was purified by preparativereverse phase HPLC on a Waters Autopurification system using a SunfirePrep C18 OBD column [5 μm, 19×50 mm; flow rate, 20 mL/min; Solvent A:H₂O with 0.1% HCO₂H; Solvent B: CH₃CN with 0.1% HCO₂H; injection volume:3.0 mL (CH₃CN); gradient: 20→100% B in A over 10 min; mass-directedfraction collection]. Fractions containing the desired product, elutingat 5.6-6.5 min, were collected and freeze-dried to yield compoundS16-8-1 (19 mg, 37% for 2 steps): ¹H NMR (400 MHz, CDCl₃) δ 7.50-7.48(m, 4H), 7.39-7.26 (m, 6H), 7.06 (s, 1H), 5.35 (s, 2H), 5.23, 5.17 (ABq,J=12.8 Hz, 2H), 4.04 (d, J=10.4 Hz, 1H), 3.81, 3.63 (ABq, J=13.4 Hz,2H), 3.09 (dd, J=4.3, 15.3 Hz, 1H), 2.88-2.76 (m, 7H), 2.53-2.46 (m,9H), 2.11 (d, J=13.4 Hz, 1H), 1.14 (s, 9H), 0.83 (s, 9H), 0.27 (s, 3H),0.14 (s, 3H); MS (ESI) m/z 835.48 (M+H).

Aqueous HF (48-50%, 0.2 mL) was added to a solution of compound S16-9-1(19 mg, 0.024 mmol, 1.0 equiv) in acetonitrile (0.6 mL) in apolypropylene reaction vessel at 23° C. The mixture was stirredvigorously at 23° C. overnight and poured into aqueous K₂HPO₄ (2.5 gdissolved in 20 mL water). The mixture was extracted with EtOAc (2×25mL). The combined organic extracts were dried over anhydrous sodiumsulfate, filtered, and concentrated. The residue was used directly inthe next step without further purification.

Pd—C (10 wt %, 9 mg) was added in one portion into the yellow solutionof the above crude product in a mixture of HCl/MeOH (0.5 N, 0.14 mL, 3.0equiv) and MeOH (2 mL) at 23° C. The reaction vessel was sealed andpurged with hydrogen by briefly evacuating the flask followed byflushing with hydrogen gas (1 atm). The resulting mixture was stirred at23° C. for 30 min. The reaction mixture was then filtered through asmall Celite pad. The filtrate was concentrated. The residue waspurified by preparative reverse phase HPLC on a Waters Autopurificationsystem using a Phenomenex Polymerx 10μ RP-γ 100A column [10 μm,150×21.20 mm; flow rate, 20 mL/min; Solvent A: 0.05 N HCl/water; SolventB: CH₃CN; injection volume: 3.0 mL (0.05 N HCl/water); gradient: 15-60%B over 10 min; mass-directed fraction collection]. Fractions containingthe desired product, eluting at 5.8-8.0 min, were collected andfreeze-dried to yield compound S16-10-1 (11 mg, 67% for 2 steps): ¹H NMR(400 MHz, CD₃OD) δ 7.01 (s, 1H), 4.36 (d, J=12.8 Hz, 1H), 4.14 (d,J=12.8 Hz, 1H), 4.12 (s, 1H), 3.11-2.83 (m, 15H), 2.45 (t, J=14.2 Hz,1H), 2.29-2.26 (m, 1H), 1.70-1.60 (m, 1H), 1.47 (s, 9H); MS (ESI) m/z543.31 (M+H).

The following compounds were prepared similarly to S16-8-1 or S16-10-1.

S16-8-2:

¹H NMR (400 MHz, CDCl₃) δ 7.44-7.41 (m, 4H), 7.33-7.23 (m, 6H), 7.11 (s,1H), 5.29 (s, 2H), 5.23, 5.15 (ABq, J=12.8 Hz, 2H), 4.07 (d, J=14.0 Hz,1H), 3.96 (d, J=10.4 Hz, 1H), 3.80 (d, J=14.0 Hz, 1H), 2.96 (dd, J=4.3,15.9 Hz, 1H), 2.83-2.71 (m, 8H), 2.51-2.36 (m, 11H), 2.05 (d, J=14.6 Hz,1H), 0.77 (s, 9H), 0.21 (s, 3H), 0.08 (s, 3H); MS (ESI) m/z 793.35(M+H).

S16-8-3:

¹H NMR (400 MHz, CDCl₃) δ 7.50-7.47 (m, 4H), 7.39-7.28 (m, 6H), 7.15 (s,1H), 5.35 (s, 2H), 5.28, 5.21 (ABq, J=12.8 Hz, 2H), 4.11 (d, J=14.0 Hz,1H), 4.02 (d, J=10.4 Hz, 1H), 3.84 (d, J=14.0 Hz, 1H), 3.02 (dd, J=4.9,15.9 Hz, 1H), 2.88-2.76 (m, 8H), 2.66 (q, J=7.3 Hz, 2H), 2.56-2.44 (m,8H), 2.11 (d, J=14.0 Hz, 1H), 1.19 (t, J=7.3 Hz, 3H), 0.83 (s, 9H), 0.27(s, 3H), 0.14 (s, 3H); MS (ESI) m/z 807.37 (M+H).

S16-8-4:

¹H NMR (400 MHz, CDCl₃) δ 7.50-7.47 (m, 4H), 7.39-7.31 (m, 5H),7.28-7.24 (m, 1H), 7.00 (s, 1H), 5.35 (s, 2H), 5.23, 5.18 (ABq, J=12.2Hz, 2H), 4.05 (d, J=10.4 Hz, 1H), 3.88, 3.65 (ABq, J=14.6 Hz, 2H), 3.10(dd, J=4.3, 15.9 Hz, 1H), 2.93-2.74 (m, 7H), 2.54-2.44 (m, 9H), 2.33 (d,J=6.7 Hz, 2H), 2.12 (d, J=14.0 Hz, 1H), 1.76-1.69 (m, 1H), 0.88 (d,J=6.7 Hz, 6H), 0.84 (s, 9H), 0.28 (s, 3H), 0.15 (s, 3H); MS (ESI) m/z835.50 (M+H).

S16-8-5:

¹H NMR (400 MHz, CDCl₃) δ 7.50-7.47 (m, 4H), 7.39-7.24 (m, 6H), 7.21 (s,1H), 5.35 (s, 2H), 5.24, 5.19 (ABq, J=12.8 Hz, 2H), 4.06-3.99 (m, 2H),3.76-3.73 (m, 1H), 3.08 (dd, J=4.3, 15.3 Hz, 1H), 2.89-2.71 (m, 8H),2.55-2.46 (m, 8H), 2.31-2.26 (m, 2H), 2.11 (d, J=13.4 Hz, 1H), 0.92 (s,9H), 0.83 (s, 9H), 0.27 (s, 3H), 0.14 (s, 3H); MS (ESI) m/z 849.40(M+H).

S16-8-6:

¹H NMR (400 MHz, CDCl₃) δ 7.50-7.48 (m, 4H), 7.39-7.31 (m, 5H),7.28-7.24 (m, 1H), 7.08 (s, 1H), 5.35 (s, 2H), 5.23, 5.19 (ABq, J=12.8Hz, 2H), 4.05 (d, J=10.4 Hz, 1H), 3.73, 3.57 (ABq, J=13.4 Hz, 2H), 3.10(dd, J=4.3, 15.3 Hz, 1H), 2.92-2.76 (m, 7H), 2.53-2.45 (m, 9H), 2.11 (d,J=13.4 Hz, 1H), 1.44 (q, J=7.3 Hz, 2H), 1.06 (s, 6H), 0.86 (t, J=7.3 Hz,3H), 0.84 (s, 9H), 0.28 (s, 3H), 0.14 (s, 3H); MS (ESI) m/z 849.43(M+H).

S16-8-7:

¹H NMR (400 MHz, CDCl₃) δ 7.50-7.48 (m, 4H), 7.39-7.31 (m, 5H),7.28-7.26 (m, 1H), 7.08 (s, 1H), 5.35 (s, 2H), 5.24, 5.18 (ABq, J=12.8Hz, 2H), 4.05 (d, J=10.4 Hz, 1H), 3.90, 3.71 (ABq, J=13.4 Hz, 2H), 3.11(dd, J=4.3, 15.9 Hz, 1H), 2.92-2.76 (m, 7H), 2.54-2.43 (m, 9H), 2.11 (d,J=14.0 Hz, 1H), 0.98 (d, J=2.4 Hz, 6H), 0.83 (s, 9H), 0.39-0.34 (m, 2H),0.27 (s, 3H), 0.25-0.22 (m, 2H), 0.14 (s, 3H); MS (ESI) m/z 861.39(M+H).

S16-8-8:

¹H NMR (400 MHz, CDCl₃) δ 16.11 (br s, 1H), 7.51-7.48 (m, 4H), 7.39-7.30(m, 6H), 7.26 (s, 1H), 5.35 (s, 2H), 5.28, 5.21 (ABq, J=12.8 Hz, 2H),4.04 (d, J=10.4 Hz, 1H), 3.57 (br s, 2H), 3.12 (dd, J=3.7, 15.3 Hz, 1H),2.92-2.72 (m, 7H), 2.54-2.43 (m, 9H), 2.26 (s, 6H), 2.11 (d, J=1.34 Hz,1H), 0.83 (s, 9H), 0.27 (s, 3H), 0.14 (s, 3H); MS (ESI) m/z 807.32(M+H).

S16-8-9:

¹H NMR (400 MHz, CDCl₃) δ 16.12 (br s, 1H), 7.50-7.46 (m, 4H), 7.39-7.28(m, 6H), 7.23 (s, 1H), 5.35 (s, 2H), 5.26 (s, 2H), 4.05 (d, J=10.4 Hz,1H), 3.58 (br s, 2H), 3.15-3.12 (m, 1H), 2.92-2.85 (m, 1H), 2.77-2.70(m, 7H), 2.53-2.43 (m, 9H), 2.31-2.27 (m, 2H), 2.12-2.04 (m, 3H), 0.88(s, 9H), 0.84 (s, 9H), 0.28 (s, 3H), 0.15 (s, 3H); MS (ESI) m/z 863.44(M+H).

S16-8-10:

¹H NMR (400 MHz, CDCl₃) δ 16.04 (br s, 1H), 7.40-7.38 (m, 2H), 7.34-7.32(m, 2H), 7.29-7.19 (m, 5H), 7.15-7.14 (m, 1H), 7.11 (s, 1H), 5.26 (s,2H), 5.12 (s, 2H), 3.97 (d, J=10.4 Hz, 1H), 3.76 (d, J=15.9 Hz, 1H),3.58 (d, J=15.9 Hz, 1H), 3.04 (dd, J=4.3, 15.9 Hz, 1H), 2.84-2.78 (m,1H), 2.69 (s, 3H), 2.62 (s, 3H), 2.43-2.28 (m, 11H), 2.02 (d, J=14.0 Hz,1H), 1.76-1.75 (m, 1H), 0.75 (s, 9H), 0.73 (s, 9H), 0.18 (s, 3H), 0.06(s, 3H), 0.03-0.09 (m, 4H); MS (ESI) m/z 899.48 (M+H).

S16-8-11:

¹H NMR (400 MHz, CDCl₃) δ 16.14 (br s, 1H), 7.50-7.45 (m, 4H), 7.39-7.31(m, 5H), 7.25-7.21 (m, 2H), 5.36 (s, 2H), 5.22 (s, 2H), 4.05 (d, J=10.4Hz, 1H), 3.53, 3.46 (ABq, J=15.3 Hz, 2H), 3.18 (dd, J=3.7, 15.3 Hz, 1H),2.92-2.86 (m, 1H), 2.81-2.71 (m, 6H), 2.53-2.31 (m, 11H), 2.11 (d,J=13.4 Hz, 1H), 1.64 (br s, 4H), 1.62 (s, 3H), 0.98 (s, 3H), 0.84 (s,9H), 0.28 (s, 3H), 0.15 (s, 3H); MS (ESI) m/z 861.49 (M+H).

S16-10-2:

¹H NMR (400 MHz, CD₃OD) δ 6.89 (s, 1H), 4.37 (d, J=13.7 Hz, 1H), 4.12(d, J=13.7 Hz, 1H), 4.10 (s, 1H), 3.10-2.78 (m, 18H), 2.43 (t, J=14.6Hz, 1H), 2.27-2.24 (m, 1H), 1.70-1.60 (m, 1H); MS (ESI) m/z 501.29(M+H).

S16-10-3:

¹H NMR (400 MHz, CD₃OD) δ 6.94 (s, 1H), 4.38 (d, J=13.7 Hz, 1H), 4.15(d, J=14.2 Hz, 1H), 4.11 (s, 1H), 3.16 (q, J=7.3 Hz, 2H), 3.12-2.81 (m,15H), 2.44 (t, J=14.2 Hz, 1H), 2.28-2.25 (m, 1H), 1.69-1.60 (m, 1H),1.37 (t, J=7.3 Hz, 3H); MS (ESI) m/z 515.30 (M+H).

S16-10-4:

¹H NMR (400 MHz, CD₃OD) δ 7.05 (s, 1H), 4.50 (d, J=13.3 Hz, 1H), 4.26(d, J=13.7 Hz, 1H), 4.15 (s, 1H), 3.18-2.89 (m, 17H), 2.52 (t, J=12.8Hz, 1H), 2.34-2.31 (m, 1H), 2.15-2.08 (m, 1H), 1.70-1.61 (m, 1H), 1.06(d, J=6.4 Hz, 6H); MS (ESI) m/z 543.32 (M+H).

S16-10-5:

¹H NMR (400 MHz, CD₃OD) δ 6.93 (s, 1H), 4.42 (d, J=13.7 Hz, 1H), 4.17(d, J=13.7 Hz, 1H), 4.10 (s, 1H), 3.04-2.83 (m, 17H), 2.47 (t, J=14.6Hz, 1H), 2.28-2.24 (m, 1H), 1.70-1.60 (m, 1H), 1.08 (s, 9H); MS (ESI)m/z 557.31 (M+H).

S16-10-6:

¹H NMR (400 MHz, CD₃OD) δ 7.03 (s, 1H), 4.38 (d, J=12.8 Hz, 1H), 4.16(d, J=12.8 Hz, 1H), 4.14 (s, 1H), 3.13-2.87 (m, 15H), 2.47 (t, J=14.6Hz, 1H), 2.31-2.28 (m, 1H), 1.82 (q, J=7.3 Hz, 2H), 1.70-1.61 (m, 1H),1.44 (s, 6H), 1.05 (t, J=7.3 Hz, 3H); MS (ESI) m/z 557.32 (M+H).

S16-10-7:

¹H NMR (400 MHz, CD₃OD) δ 7.04 (s, 1H), 4.50 (d, J=13.3 Hz, 1H), 4.26(d, J=13.3 Hz, 1H), 4.14 (s, 1H), 3.12-2.86 (m, 15H), 2.46 (t, J=14.2Hz, 1H), 2.31-2.27 (m, 1H), 1.70-1.61 (m, 1H), 1.34 (s, 6H), 1.25-1.19(m, 1H), 0.72-0.59 (m, 4H); MS (ESI) m/z 569.30 (M+H).

S16-10-8:

¹H NMR (400 MHz, CD₃OD) δ 6.96 (s, 1H), 4.55 (d, J=13.3 Hz, 1H), 4.23(d, J=13.3 Hz, 1H), 4.12 (s, 1H), 3.09-2.82 (m, 21H), 2.47 (t, J=15.1Hz, 1H), 2.28-2.25 (m, 1H), 1.70-1.60 (m, 1H); MS (ESI) m/z 515.28(M+H).

S16-10-9:

¹H NMR (400 MHz, CD₃OD) δ 6.99 (s, 1H), 4.74 (d, J=12.8 Hz, 0.7H), 4.54(br d, J=12.8 Hz, 0.3H), 4.38 (br d, J=12.8 Hz, 0.3H), 4.17 (d, J=12.8Hz, 0.3H), 4.11 (s, 1H), 3.20-2.80 (m, 20H), 2.55-2.48 (m, 1H),2.29-2.26 (m, 1H), 1.70-1.61 (m, 1H), 1.10 (s, 9H); MS (ESI) m/z 571.38(M+H).

S16-10-10:

¹H NMR (400 MHz, CD₃OD) δ 7.08 (s, 1H), 4.72 (d, =12.8 Hz, 1H), 4.42 (d,J=12.8 Hz, 1H), 4.10 (s, 1H), 3.09-2.85 (m, 18H), 2.51 (t, J=15.6 Hz,1H), 2.28-2.24 (m, 1H), 1.71-1.62 (m, 1H), 1.13 (s, 9H), 1.08-1.06 (m,4H); MS (ESI) m/z 597.38 (M+H).

S16-10-11:

¹H NMR (400 MHz, CD₃OD) δ 6.99 (s, 0.4H), 6.97 (s, 0.6H), 4.68 (d,J=12.8 Hz, 0.6H), 4.43 (d, J=12.8 Hz, 0.4H), 4.19 (d, J=12.8 Hz, 0.4H),4.10 (s, 1H), 3.93 (d, J=12.8 Hz, 0.6H), 3.08-2.80 (m, 17H), 2.48 (t,J=16.0 Hz, 1H), 2.28-2.24 (m, 1H), 2.16-2.14 (m, 2H), 2.04-1.99 (m, 2H),1.71-1.61 (m, 1H), 1.61 (s, 3H), 1.44 (s, 3H); MS (ESI) m/z 569.32(M+H).

S16-10-12:

¹H NMR (400 MHz, CD₃OD) δ 6.96 (s, 1H), 4.81 (dt, J=47.2, 4.1 Hz, 2H),4.49 (d, J=14.2 Hz, 1H), 4.26 (d, J=14.2 Hz, 1H), 4.13 (s, 1H), 3.49(dt, J=26.6, 3.7 Hz, 2H), 3.12-2.85 (m, 15H), 2.46 (t, J=14.2 Hz, 1H),2.30-2.27 (m, 1H), 1.70-1.60 (m, 1H); MS (ESI) m/z 533.31 (M+H).

S16-10-13:

¹H NMR (400 MHz, CD₃OD) δ 6.94 (s, 1H), 6.37 (tt, J=2.8, 53.6 Hz, 1H),4.52 (d, J=14.2 Hz, 1H), 4.29 (d, J=14.2 Hz, 1H), 4.13 (s, 1H), 3.64 (t,J=15.6 Hz, 2H), 3.12-2.85 (m, 15H), 2.47 (t, J=14.2 Hz, 1H), 2.31-2.27(m, 1H), 1.70-1.60 (m, 1H); MS (ESI) m/z 551.27 (M+H).

S16-10-14:

¹H NMR (400 MHz, CD₃OD) δ 6.95 (s, 1H), 4.42 (d, J=14.2 Hz, 1H), 4.19(d, J=14.2 Hz, 1H), 4.12 (s, 1H), 3.07-2.97 (m, 17H), 2.44 (t, J=14.2Hz, 1 H), 2.28-2.25 (m, 1H), 1.70-1.60 (m, 1H), 1.21-1.14 (m, 1H),0.77-0.73 (m, 2H), 0.46-0.42 (m, 2H); MS (ESI) m/z 541.29 (M+H).

S16-10-15:

¹H NMR (400 MHz, CD₃OD) δ 6.93 (s, 1H), 4.39 (d, J=13.7 Hz, 1H), 4.14(d, J=13.7 Hz, 1H), 4.10 (s, 1H), 3.10-2.81 (m, 17H), 2.45 (t, J=14.6Hz, 1H), 2.28-2.24 (m, 1H), 1.84-1.64 (m, 6H), 1.39-1.21 (m, 4H),1.10-1.04 (m, 2H); MS (ESI) m/z 583.34 (M+H).

S16-10-16:

¹H NMR (400 MHz, CD₃OD) δ 6.93 (s, 1H), 4.40 (d, J=13.7 Hz, 1H), 4.16(d, J=13.7 Hz, 1H), 4.12 (s, 1H), 3.10-2.77 (m, 17H), 2.47 (t, J=14.6Hz, 1H), 2.29-2.26 (m, 1H), 2.04 (br s, 3H), 1.82-1.70 (m, 7H),1.66-1.64 (m, 6H); MS (ESI) m/z 635.34 (M+H).

S16-10-17:

¹H NMR (400 MHz, CD₃OD) δ 6.93 (s, 1H), 4.49 (d, J=13.7 Hz, 1H), 4.27(d, J=13.7 Hz, 1H), 4.10 (s, 1H), 3.10-2.81 (m, 16H), 2.43 (t, J=14.2Hz, 1H), 2.27-2.24 (m, 1H), 1.69-1.60 (m, 1H), 0.95-0.94 (m, 4H); MS(ESI) m/z 527.35

S16-10-18:

¹H NMR (400 MHz, CD₃OD) δ 6.98 (s, 1H), 4.44 (d, J=13.3 Hz, 1H), 4.16(d, J=13.7 Hz, 1H), 4.12 (s, 1H), 3.45 (s, 1H), 3.08-2.85 (m, 15H), 2.48(t, J=14.6 Hz, 1H), 2.30-2.23 (m, 3H), 2.06-1.94 (m, 6H), 1.85-1.79 (m,6H), 1.73-1.61 (m, 1H); MS (ESI) m/z 621.35 (M+H).

S16-10-19:

¹H NMR (400 MHz, CD₃OD) δ 6.97 (s, 1H), 4.64 (d, J=13.3 Hz, 0.5H), 4.48(d, J=13.3 Hz, 0.5H), 4.32 (d, J=13.3 Hz, 0.5H), 4.12 (s, 1H), 4.11 (d,J=12.8 Hz, 0.5H), 3.22-2.82 (m, 20H), 2.47 (t, J=14.6 Hz, 1H), 2.29-2.25(m, 1H), 1.70-1.61 (m, 1H), 1.44-1.37 (m, 3H); MS (ESI) m/z 529.30(M+H).

S16-10-20:

¹H NMR (400 MHz, CD₃OD) δ 6.98 (s, 0.4H), 6.96 (s, 0.6H), 4.86 (br s,0.4H), 4.72 (d, J=13.3 Hz, 0.6H), 4.43 (br s, 0.6H), 4.13-4.60 (m,1.4H), 3.25-2.87 (m, 20H), 2.51-2.47 (m, 1H), 2.27 (br s, 2H), 1.66 (brs, 1H), 1.08 (d, J=4.1 Hz, 6H); MS (ESI) m/z 557.32 (M+H).

S16-10-21:

¹H NMR (400 MHz, CD₃OD) δ 6.96 (s, 0.4H), 6.94 (s, 0.6H), 4.72 (d,J=13.3 Hz, 0.4H), 4.42 (s, 0.6H), 4.09 (s, 1H), 4.09 (d, J=13.3 Hz,0.4H), 3.08-2.81 (m, 20H), 2.50-2.38 (m, 1H), 2.27-2.24 (m, 1H),1.71-1.57 (m, 5H), 1.38-1.28 (m, 4H); MS (ESI) m/z 583.38 (M+H).

S16-10-22:

¹H NMR (400 MHz, CD₃OD) δ 6.99 (s, 0.4H), 6.69 (s, 0.6H), 4.81 (d,J=13.3 Hz, 0.6H), 4.54 (d, J=12.8 Hz, 0.4H), 4.24 (d, J=12.8 Hz, 0.4H),4.12 (s, 1H), 3.96 (d, J=13.3 Hz, 0.6H), 3.05-2.72 (m, 18H), 2.54-2.47(m, 1H), 2.30-2.26 (m, 1H), 1.71-1.62 (m, 1H), 1.55 (s, 9H); MS (ESI)m/z 557.31 (M+H).

S16-10-23:

¹H NMR (400 MHz, CD₃OD) δ 6.98 (s, 0.35H), 6.95 (s, 0.75H), 4.92 (d,J=13.3 Hz, 0.75H), 4.56 (d, J=12.8 Hz, 0.35H), 4.24 (d, J=12.8 Hz,0.35H), 4.13 (s, 1H), 4.00 (d, J=13.3 Hz, 0.75H), 3.12-2.73 (m, 18H),2.55-2.46 (m, 1H), 2.31-2.28 (m, 1H), 2.02-1.82 (m, 2H), 1.71-1.61 (m,1H), 1.53-1.49 (m, 6H), 1.09 (t, J=7.3 Hz, 3H); MS (ESI) m/z 571.31(M+H).

S16-10-24:

¹H NMR (400 MHz, CD₃OD) δ 7.01 (s, 0.4H), 6.96 (s, 0.6H), 4.68 (d,J=12.8 Hz, 0.4H), 4.32 (d, J=12.8 Hz, 0.4H), 4.13 (s, 1H), 4.05 (d,J=13.3 Hz, 0.6H), 3.25-2.80 (m, 18H), 2.55-2.43 (m, 1H), 2.32-2.28 (m,1H), 1.71-1.62 (m, 1H), 1.42-1.38 (m, 6H), 1.31-1.28 (m, 1H), 0.80-0.78(m, 2H), 0.68-0.64 (m, 2H); MS (ESI) m/z 583.32 (M+H).

S16-10-25:

¹H NMR (400 MHz, CD₃OD) δ7.02 (s, 1H), 4.71 (d, J=13.3 Hz, 1H), 4.42 (d,J=13.3 Hz, 1H), 4.12 (s, 1H), 3.14-2.82 (m, 18H), 2.49 (t, J=15.6 Hz,1H), 2.40-2.33 (m, 1H), 2.29-2.26 (m, 1H), 1.70-1.61 (m, 1H), 1.07-0.99(m, 10H); MS (ESI) m/z 583.36 (M+H).

S16-10-26:

¹H NMR (400 MHz, CD₃OD) δ 7.01 (s, 1H), 5.46 (br d, J=52.2 Hz, 1H), 4.72(d, J=13.3 Hz, 1H), 4.39 (br s, 1H), 4.12 (s, 1H), 3.85 (br s, 2H),3.55-3.46 (m, 2H), 3.12-2.84 (m, 15H), 2.51-2.43 (m, 3H), 2.30-2.26 (m,1H), 1.70-1.60 (m, 1H); MS (ESI) m/z 559.26 (M+H).

S16-10-27:

¹H NMR (400 MHz, CD₃OD) δ 7.04 (s, 1H), 4.56 (d, J=12.8 Hz, 1H), 4.30(d, J=12.8 Hz, 1H), 4.12 (s, 1H), 3.36-2.83 (m, 19H), 2.47 (t, J=14.2Hz, 1H), 2.29-2.26 (m, 1H), 1.77-1.61 (m, 5H), 1.11 (s, 3H), 1.05 (s,3H); MS (ESI) m/z 583.36 (M+H).

S16-10-28:

¹H NMR (400 MHz, CD₃OD) δ 7.00 (s, 1H), 4.58 (d, J=14.0 Hz, 1H), 4.24(d, J=13.2 Hz, 1H), 4.13 (s, 1H), 3.28-3.24 (m, 4H), 3.09-2.80 (m, 15H),2.60-2.48 (m, 1H), 2.32-2.28 (m, 1H), 1.68-1.63 (m, 1H), 0.93-0.85 (m,6H); MS (ESI) m/z 543.1 (M+H).

S16-10-29:

¹H NMR (400 MHz, CD₃OD) δ 6.97 (s, 1H), 5.00-4.95 (m, 1H), 4.85-4.800(m, 1H), 4.78-4.58 (m, 1H), 4.48-4.24 (m, 1H), 4.14 (s, 1H), 3.68-3.49(m, 2H), 3.12-2.87 (m, 18H), 2.61-2.49 (m, 1H), 2.32-2.29 (m, 1H),1.69-1.63 (m, 1H); MS (ESI) m/z 547.0 (M+H).

S16-10-30:

¹H NMR (400 MHz, CD₃OD) δ 7.00 (s, 1H), 5.08-5.02 (m, 1H), 4.90-4.85 (m,1H), 4.76-4.72 (m, 1H), 4.39-4.36 (m, 1H), 4.15 (s, 1H), 3.67-3.60 (m,2H), 3.16-2.91 (m, 17H), 2.62-2.48 (m, 1H), 2.34-2.31 (m, 1H), 1.72-1.69(m, 1H), 1.49-1.38 (m, 3H); MS (ESI) m/z 561.1 (M+H).

S16-10-31:

¹H NMR (400 MHz, CD₃OD) δ 6.92 (s, 1H), 6.40 (t, J=54.0 Hz, 1H), 4.56(d, J=13.2 Hz, 1H), 4.21 (d, J=13.6 Hz, 1H), 4.12 (s, 1H), 3.40-3.57 (m,3H), 3.21-2.90 (m, 16H), 2.70-2.62 (m, 1H), 2.39-2.27 (m, 1H), 1.76-1.58(m, 1H); MS (ESI) m/z 565.1 (M+H).

S16-10-32:

¹H NMR (400 MHz, CD₃OD) δ 6.97 (s, 1H), 6.42 (t, J=54.0 Hz, 1H), 4.60(d, J=15.2 Hz, 1H), 4.30 (d, J=15.2 Hz, 1H), 4.16 (s, 1H), 3.63-3.52 (m,2H), 3.24-3.00 (m, 17H), 2.66-2.52 (m, 1H), 2.39-2.36 (m, 1H), 1.71-1.65(m, 1H), 1.31 (t, J=6.8 Hz, 3H); MS (ESI) m/z 579.1 (M+H).

S16-10-33:

¹H NMR (400 MHz, CD₃OD) δ 6.90 (s, 1H), 4.45 (d, J=15.2 Hz, 1H), 4.26(d, J=15.2 Hz, 1H), 4.12 (s, 1H), 3.81 (m, 2H), 3.20-2.96 (m, 15H),2.64-2.52 (m, 1H), 2.36-2.31 (m, 1H), 1.69-1.55 (m, 1H); MS (ESI) m569.2 (M+H).

S16-10-34:

¹H NMR (400 MHz, CD₃OD) δ 6.89 (s, 1H), 4.43 (d, J=15.2 Hz, 1H), 4.14(s, 1H), 4.07 (d, J=15.2 Hz, 1H), 3.64-3.54 (m, 2H), 3.42 (s, 3H), 3.31(s, 3H), 3.19-2.94 (m, 9H), 2.63 (t, J=28.8, 14.4 Hz, 1H), 2.60 (s, 3H),2.41-2.37 (m, 1H), 1.69-1.59 (m, 1H); MS (ESI) m/z 583.1 (M+H).

S16-10-35:

¹H NMR (400 MHz, CD₃OD) δ 6.95 (s, 1H), 4.43 (d, J=15.6 Hz, 1H), 4.18(d, J=15.6 Hz, 1H), 4.16 (s, 1H), 3.66-3.53 (m, 2H), 3.47 (s, 3H), 3.35(s, 3H), 3.19-2.82 (m, 11H), 2.68-2.55 (m, 1H), 2.42-2.39 (m, 1H),1.70-1.62 (m, 1H), 1.17 (t, J=7.2 Hz, 3H); MS (ESI) m/z 597.1 (M+H).

S16-10-36:

¹H NMR (400 MHz, CD₃OD) δ 6.90 (s, 1H), 4.35 (d, J=14.0 Hz, 1H), 4.12(d, J=14.0 Hz, 1H), 4.08 (s, 1H), 3.08-2.75 (m, 17H), 2.48-2.38 (m, 1H),2.28-2.23 (m, 1H), 1.78-1.73 (m, 2H), 1.63-1.58 (m, 1H), 1.03-0.98 (m,3H); MS (ESI) m/z 529.3 (M+H).

S16-10-37:

¹H NMR (400 MHz, CD₃OD) δ 6.89, 6.88 (s, 1H total), 4.58, 4.39 (d,J=13.6 Hz, 1H, total), 4.26, 4.03 (d, J=13.6 Hz, 1H, total), 4.03 (s,1H), 3.12-2.72 (m, 20H), 2.43-2.34 (m, 1H), 2.21-2.18 (m, 1H), 1.78-1.75(m, 2H), 1.61-1.51 (m, 1H), 0.97-0.90 (m, 3H); MS (ESI) m/z 543 (M+H.

S16-10-38:

¹H NMR (400 MHz, CD₃OD) δ 6.85 (s, 1H), 4.52-4.47 (m, 1H), 4.18-4.15 (m,1H), 4.07 (s, 1H), 3.16-2.75 (m, 19H), 2.41-2.34 (m, 1H), 2.28-2.25 (m,1H), 1.74-1.73 (m, 2H), 1.60-1.50 (m, 1H), 1.30-1.25 (m, 3H), 0.96-0.92(m, 3H); MS (ESI) m/z 557.1 (M+H).

S16-10-39:

¹H NMR (400 MHz, CD₃OD) δ 6.91 (s, 1H), 4.46 (d, J=14.4 Hz, 1H), 4.13(d, J=14.4 Hz, 1H), 4.08 (s, 1H), 3.08-2.63 (m, 17H), 2.47-2.38 (m, 1H),2.27-2.22 (m, 1H), 1.75-1.68 (m, 2H), 1.67-1.62 (m, 1H), 1.44-1.42 (m,2H), 0.98 (t, J=7.2 Hz, 3H); MS (ESI) m/z 543.0 (M+H).

S16-10-40:

¹H NMR (400 MHz, CD₃OD) δ 6.96, 6.95 (s, 1H total), 4.66, 4.46 (d,J=13.6 Hz, 1H total), 4.34, 4.11 (d, J=13.6 Hz, 1H total), 4.11 (s, 1H),3.20-2.79 (m, 20H), 2.50-2.41 (m, 1H), 2.28-2.24 (m, 1H), 1.81-1.75 (m,2H), 1.68-1.59 (m, 1H), 1.45-1.38 (m, 2H), 0.97 (m, 3H); MS (ESI) m/z557.3 (M+H).

S16-10-41:

¹H NMR (400 MHz, CD₃OD) δ 6.99, 6.98 (s, 1H, total), 4.82, 4.67 (d,J=13.6 Hz, 1H, total), 4.43, 4.30 (d, J=13.6 Hz, 1H, total), 4.15 (s,1H), 3.22-2.88 (m, 19H), 2.58-2.51 (m, 1H), 2.35-2.30 (m, 1H), 1.87-1.79(m, 1H), 1.75-1.65 (m, 1H), 1.49-1.38 (m, 2H), 1.35-1.145 (m, 2H),1.03-0.95 (m, 3H), 0.88-0.81 (m, 2H), 0.51-0.40 (m, 2H); MS (ESI) m/z597.1 (M+H).

S16-10-42:

¹H NMR (400 MHz, CD₃OD) δ 6.96 (s, 1H), 4.42 (d, J=14.4 Hz, 1H), 4.18(d, J=14.4 Hz, 1H), 4.13 (s, 1H), 3.14-2.84 (m, 17H), 2.51-2.39 (m, 1H),2.31-2.25 (m, 1H), 1.68-1.64 (m, 4H), 0.99-0.96 (m, 6H); MS (ESI) m/z557.3 (M+H).

S16-10-43:

¹H NMR (400 MHz, CD₃OD) δ 6.99, 6.97 (s, 1H, total), 4.69, 4.50 (d,J=13.2 Hz, 1H, total), 4.37, 4.14 (d, J=13.2 Hz, 1H, total), 4.12 (s,1H), 3.09, 2.82 (m, 20H), 2.54-2.45 (m, 1H), 2.30-2.26 (m, 1H),1.76-1.62 (m, 4H), 1.01-0.97 (m, 6H); MS (ESI) m/z 571.3 (M+H).

S16-10-44:

¹H NMR (400 MHz, CD₃OD) δ 6.97, 6.96 (s, 1H, total), 4.60 (d, J=13.2 Hz,1H), 4.24 (d, J=13.2 Hz, 1H), 4.12 (s, 1H), 3.23-3.15 (m, 4H), 3.13-2.84(m, 15H), 2.56-2.41 (m, 1H), 2.30-2.26 (m, 1H), 1.68-1.64 (m, 4H),1.39-1.34 (m, 3H), 0.97 (d, J=6.4 Hz, 6H); MS (ESI) m/z 585.1 (M+H).

S16-10-45:

¹H NMR (400 MHz, CD₃OD) δ 6.96 (s, 1H), 4.62-4.56 (m, 1H), 4.25-4.22 (m,1H), 4.12-4.11 (m, 1H), 3.26-2.83 (m, 19H), 2.55-2.41 (m, 1H), 2.29-2.26(m, 1H), 1.76-1.63 (m, 4H), 1.45-1.37 (m, 7H), 1.00-0.95 (m, 4H); MS(ESI) m/z 611.1 (M+H).

S16-10-46:

¹H NMR (400 MHz, CD₃OD) δ 6.85 (s, 1H), 4.28 (d, J=14.8 Hz, 1H), 4.05(d, J=14.4 Hz, 1H), 4.03 (s, 1H), 3.05-2.72 (m, 17H), 2.38-2.31 (m, 1H),2.20-2.17 (m, 1H), 1.67-1.53 (m, 8H), 1.31-1.06 (m, 4H), 0.95-0.85 (m,2H); MS (ESI) m/z 597.1 (M+H).

S16-10-47:

¹H NMR (400 MHz, CD₃OD) δ 6.85, 6.85 (s, 1H, total), 4.48 (d, J=13.6 Hz,1H), 4.12 (d, J=13.6 Hz, 1H), 4.01 (s, 1H), 3.25-2.70 (m, 19H),2.44-2.30 (m, 1H), 2.18-2.13 (m, 1H), 1.68-1.52 (m, 6H), 1.79-1.11 (m,8H), 0.93-0.85 (m, 3H); MS (ESI) m/z 625.1 (M+H).

S16-10-48:

¹H NMR (400 MHz, CD₃OD) δ 7.39-7.27 (m, 5H), 6.91 (s, 1H), 4.40 (d,J=14.8 Hz, 1H), 4.18 (d, J=14.6 Hz, 1H), 4.11 (s, 1H), 3.42-3.38 (m,2H), 3.15-2.97 (m, 9H), 2.88-2.58 (m, 6H), 2.44-2.36 (m, 1H), 2.27-2.24(m, 1H), 1.64-1.58 (m, 1H); MS (ESI) m/z 591.1 (M+H).

S16-10-49:

¹H NMR (400 MHz, CD₃OD) δ 6.83 (s, 1H), 4.30 (d, J=14.4 Hz, 1H), 4.07(d, J=14.4 Hz, 1H), 3.99 (s, 1H), 3.05-2.77 (m, 17H), 2.45-2.31 m, 1H),2.17-2.18 (m, 1H), 1.59-1.54 (m, 3H), 0.89 (s, 9H); MS (ESI) m/z 571.1(M+H).

S16-10-50:

¹H NMR (400 MHz, CD₃OD) δ 7.02, 6.99 (s, 1H, total), 4.71, 4.54 (d,J=13.2 Hz, 1H, total), 4.40, 4.17 (d, J=13.2 Hz, 1H, total), 4.14 (s,1H), 3.11-2.84 (m, 20H), 2.60-2.48 (m, 1H), 2.32-2.29 (m, 1H), 1.77-1.63(m, 3H), 1.02, 0.99 (s, 9H, total); MS (ESI) m/z 585.1 (M+H).

S16-10-51:

¹H NMR (400 MHz, CD₃OD) δ 6.96, 6.95 (s, 1H, total), 4.62-4.56 (m, 1H),4.28-4.22 (m, 1H), 4.10 (s, 1H), 3.25-2.81 (m, 19H), 2.53-2.40 (m, 1H),2.28-2.23 (m, 1H), 1.69-1.62 (m, 3H), 1.40-1.35 (m, 3H), 0.99, 0.97 (s,9H total); MS (ESI) m/z 599.1 (M+H).

S16-10-52:

¹H NMR (400 MHz, CD₃OD) δ 6.81 (s, 1H), 4.32 (d, J=14.0 Hz, 1H), 4.08(d, J=14.0 Hz, 1H), 4.03 (s, 1H), 3.68-3.60 (m, 3H), 3.05-2.73 (m, 17H),2.45-2.33 (m, 1H), 2.21-2.15 (m, 1H), 1.58-1.50 (m, 1H), 1.15-1.10 (m,6H); MS (ESI) m/z 573.1 (M+H).

S16-10-53:

¹H NMR (400 MHz, CD₃OD) δ 6.93, 6.91 (s, 1H total), 4.66-4.63 (m, 1H),4.31-4.25 (m, 1H), 4.11 (s, 1H), 3.82-3.70 (m, 3H), 3.55-3.51 (m, 1H),3.42-3.37 (m, 2H), 3.18-2.84 (m, 16H), 2.50-2.46 (m, 1H), 2.30-2.27 (m,1H), 1.66-1.63 (m, 1H), 1.43-1.12 (m, 9H); MS (ESI) m/z 601.1 (M+H).

S16-10-54:

¹H NMR (400 MHz, CD₃OD) δ 6.91, 6.89 (s, 1H total), 4.72-4.69 (m, 1H),4.48-4.39 (m, 1H), 4.11 (s, 1H), 3.89-3.70 (m, 3H), 3.56-3.39 (m, 4H),3.05-2.83 (m, 16H), 2.53-2.45 (m, 1H), 2.29-2.26 (m, 1H), 1.66-1.63 (m,1H), 1.27-1.20 (m, 6H); MS (ESI) m/z 586.9 (M+H).

S16-10-55:

¹H NMR (400 MHz, CD₃OD) δ 7.01 (s, 1H), 4.50-4.46 (m, 1H), 4.29-4.25 (m,1H), 4.09 (s, 1H), 3.83-3.59 (m, 6H), 3.21-2.79 (m, 17H), 2.46-2.26 (m,1H), 2.36-2.31 (m, 1H), 2.39-2.06 (m, 4H), 1.68-1.62 (m, 1H); MS (ESI)m/z 584.3 (M+H).

S16-10-56:

¹H NMR (400 MHz, CD₃OD) δ 7.12 (s, 1H), 4.66-4.62 (m, 1H), 4.36-4.34 (m,1H), 4.13 (s, 1H), 3.81-3.60 (m, 6H), 3.07-2.87 (m, 20H), 2.56-2.41 (m,1H), 2.32-2.29 (m, 1H), 2.25-2.08 (m, 4H), 1.73-1.58 (m, 1H); MS (ESI)m/z 598.1 (M+H).

S16-10-57:

¹H NMR (400 MHz, CD₃OD) δ 7.10 (s, 1H). 4.67-4.64 (m, 1H). 4.35-4.32 (m,1H), 4.13 (s, 1H), 3.82-3.60 (m, 6H), 3.14-2.89 (m, 19H), 2.556-2.42 (m,1H), 2.31-2.29 (m, 1H), 2.22-2.02 (m, 4H), 1.61-1.72 (m, 1H), 1.45-1.38(m, 3H); MS (ESI) m/z 612.3 (M+H).

S16-10-58:

¹H NMR (400 MHz, CD₃OD) δ 6.94 (s, 1H), 4.67, 4.54 (d, J=13.6 Hz, 1H,total), 4.53, 4.23 (d, J=13.6 Hz, 1H, total), 4.10 (s, 1H), 3.19-2.83(m, 19H), 2.55-2.42 (m, 1H), 2.29-2.26 (m, 1H), 2.20-2.16 (m, 1H),1.66-1.64 (m, 1H), 1.41-1.28 (m, 3H), 1.11-1.01 (m, 6H); MS (ESI) m/z571.1 (M+H).

S16-10-59:

¹H NMR (400 MHz, CD₃OD) δ 7.01, 6.98 (s, 1H, total), 4.81 (s, 1H), 4.48(s, 1H), 4.14 (s, 1H), 3.25-2.85 (m, 20H), 2.55-2.43 (m, 1H), 2.32-2.29(m, 1H), 1.69-1.63 (m, 1H), 1.30-1.20 (m, 1H), 0.89-0.81 (m, 2H),0.54-0.48 (m, 2H); MS (ESI) m/z 555.0 (M+H).

S16-10-60:

¹H NMR (400 MHz, CD₃OD) δ 6.93, 6.92 (s, 1H, total), 4.76, 4.57 (d,J=13.6 Hz, 1H, total), 4.36, 4.21 (d, J=13.6 Hz, 1H, total), 4.08 (s,1H), 3.20-2.81 (m, 19H), 2.50-2.45 (m, 1H), 2.26-2.23 (m, 1H), 1.64-1.61(m, 1H), 1.37, 1.31 (t, J=6.8 Hz, 3H, total), 1.29-1.22 (m, 1H),0.79-0.74 (m, 2H), 0.48-0.38 (m, 2H); MS (ESI) m/z 569.1 (M+H).

S16-10-61:

¹H NMR (400 MHz, CD₃OD) δ 6.90 (s, 1H), 4.33 (d, J=14.0 Hz, 1H), 4.09(d, J=14.0 Hz, 1H), 4.08 (s, 1H), 3.12-2.94 (m, 11H), 2.87-2.75 (m, 6H),2.78-2.63 (m, 1H), 2.45-2.38 (m, 1H), 2.25-2.15 (m, 3H), 2.03-1.82 (m,4H), 1.69-1.53 (m, 1H); MS (ESI) m/555.2 (M+H).

S16-10-62:

¹H NMR (400 MHz, CD₃OD) δ 6.96, 6.94 (s, 1H, total), 4.60, 4.41 (d,J=13.2 Hz, total), 4.35, 4.08 (d, J=13.2 Hz, 1H, total), 4.11 (s, 1H),3.09-2.80 (m, 20H), 2.52-2.45 (m, 1H), 2.30-2.20 (m, 3H), 2.08-2.02 (m,1H), 1.98-1.85 (m, 4H), 1.68-1.62 (m, 1H); MS (ESI) m/z 569.1 (M+H).

S16-10-63:

¹H NMR (400 MHz, CD₃OD) δ 6.96 (s, 1H), 4.57-4.55 (m, 1H), 4.25-4.23 (m,1H), 4.12 (s, 1H), 3.25-2.82 (m, 19H), 2.57-2.42 (m, 1H), 2.27-2.23 (m,3H), 2.10-2.05 (m, 1H), 2.00-1.91 (m, 4H), 1.72-1.68 (m, 1H), 1.39-1.35(m, 3H); MS (ESI) m/z 583.1 (M+H).

S16-10-64:

¹H NMR (400 MHz, CD₃OD) δ 6.99 (s, 1H), 4.46 (d, J=13.6 Hz, 1H), 4.24(d, J=13.6 Hz, 1H), 4.15 (s, 1H), 3.27-2.87 (m, 17H), 2.56-2.46 (m, 1H),2.32-2.29 (m, 1H), 1.96-1.94 (m, 6H), 1.70-1.65 (m, 3H), 0.94 (t, J=7.6Hz, 3H); MS (ESI) m/z 583.1 (M+H).

S16-10-65:

¹H NMR (400 MHz, CD₃OD) δ 6.98, 6.96 (s, 1H, total), 4.68, 4.45 (d,J=13.2 Hz, 1H, total), 4.34, 4.11 (d, J=13.2 Hz, 1H, total), 4.11 (s,1H), 3.08-2.78 (m, 20H), 2.55-2.42 (m, 1H), 2.29-2.25 (m, 1H), 2.16-2.12(m, 1H), 2.01-1.92 (m, 5H), 1.92-1.81 (m, 1H), 1.71-1.60 (m, 2H), 0.97(t, J=7.6 Hz, 3H); MS (ESI) m/z 597.1 (M+H).

S16-10-66:

¹H NMR (400 MHz, CD₃OD) δ 6.99 (s, 1H), 4.60, 4.47 (d, J=13.2 Hz, 1H,total), 4.35, 4.24 (d, J=13.2 Hz, 1H, total), 4.13 (s, 1H), 3.47-3.41(m, 1H), 3.20-2.84 (m, 18H), 2.60-2.50 (m, 1H), 2.31-2.29 (m, 1H),2.11-1.96 (m, 6H), 1.85-1.61 (m, 3H), 1.45-1.36 (m, 3H), 1.03-0.95 (m,3H); MS (ESI) m/z 611.1 (M+H).

S16-10-67:

¹H NMR (400 MHz, CD₃OD) δ 6.98 (s, 1H), 4.43 (d, J=13.2 Hz, 1H), 4.19(d, J=13.2 Hz, 1H), 4.14 (s, 1H), 3.01-2.85 (m, 17H), 2.50-2.43 (m, 1H),2.32-2.25 (m, 2H), 1.99-1.89 (m, 2H), 1.74-1.66 (m, 5H), 1.33-1.30 (m,2H); MS (ESI) m/z 569.3 (M+H).

S-16-10-68:

¹H NMR (400 MHz, CD₃OD) δ 6.94 (s, 1H), 4.61, 4.58, 4.50, 4.47 (s, 1H,total), 4.26, 4.23, 4.20, 4.17 (s, 1H, total), 4.11 (s, 1H), 3.55-3.45(m, 2H), 3.10-2.85 (m, 17H), 2.51-2.48 (m, 1H), 2.31-2.28 (m, 1H),2.05-1.75 (m, 2H), 1.66-1.62 (m, 2H), 1.46-1.30 (m, 6H), 1.12-1.01 (m,3H); MS (ESI) m/z 597.0 (M+H).

S16-10-69:

¹H NMR (400 MHz, CD₃OD) δ 6.93 (s, 1H), 4.71 (d, J=13.2 Hz, 1H), 4.38(s, 1H), 4.11 (s, 1H), 3.09-2.79 (m, 20H), 2.52-2.42 (m, 1H), 2.27-2.25(m, 1H), 1.95-1.92 (m, 1H), 1.81-1.62 (m, 6H), 1.37-1.25 (m, 3H),1.08-1.03 (m, 2H); MS (ESI) m/z 597.1 (M+H).

S16-10-70:

¹H NMR (400 MHz, CD₃OD) δ 6.97 (s, 1H), 4.71, 4.57 (d, J=13.6 Hz, 1H,total), 4.37, 4.24 (d, J=13.6 Hz, 1H, total), 4.14 (s, 1H), 3.22-2.86(m, 19H), 2.58-2.52 (m, 1H), 2.32-2.29 (m, 1H), 1.98-1.62 (m, 7H),1.45-1.33 (m, 5H), 1.33-1.25 (m, 1H), 1.20-1.05 (m, 2H) MS (ESI) m/z611.1 (M+H).

S16-10-71:

¹H NMR (400 MHz, CD₃OD) δ 6.93 (s, 1H), 4.42-4.39 (m, 1H), 4.19-4.16 (m,1H), 4.11 (s, 1H), 3.10-2.82 (m, 17H), 2.49-2.42 (m, 1H), 2.28-2.20 (m,1H), 1.68-1.25 (m, 1H), 1.09 (s, 3H); MS (ESI) m/z 597.3 (M+H).

S16-10-72:

¹H NMR (400 MHz, CD₃OD) δ 7.00 (s, 1H), 4.73, 4.72, 4.58, 4.55 (m, 1H,total), 4.39, 4.36, 4.19, 4.16 (m, 1H, total), 4.10 (s, 1H), 3.28 (s,2H), 3.13-2.78 (m, 18H), 2.52-2.40 (m, 1H), 2.29-2.26 (m, 1H), 1.70-1.60(m, 1H), 1.67-1.35 (m, 10H), 1.10 (s, 3H); MS (ESI) m/z 611.4 (M+H).

S16-10-73:

¹H NMR (400 MHz, CD₃OD) δ 6.99 (s, 1H), 4.93, 4.90, 4.62, 4.59 (s, 1H,total), 4.49, 4.46, 4.32, 4.29 (s, 1H, total), 4.15 (s, 1H), 3.17-2.85(m, 19H), 2.55 (m, 1H), 2.36-2.30 (m, 1H), 1.73-1.65 (m, 1H), 1.55-1.35(m, 13H), 1.17-1.15 (m, 3H); MS (ESI) m/z 625.1 (M+H).

S16-10-74:

¹H NMR (400 MHz, CD₃OD) δ 6.96 (s, 1H), 4.40 (d, J=14.0 Hz, 1H), 4.17(d, J=14.0 Hz, 1H), 4.14 (s, 1H), 3.06-2.84 (m, 17H), 2.55-2.42 (m, 1H),2.31-2.20 (m, 1H), 2.01-1.96 (m, 1H), 1.83-1.57 (m, 11H), 1.38-1.28 (m,2H); MS (ESI) m/z 597.1 (M+H).

S16-10-75:

¹H NMR (400 MHz, CD₃OD) δ 6.93 (s, 1H), 4.71, 4.68, 4.43, 4.40 (m, 1H,total), 4.37, 4.68, 4.06, 4.03, (m, 1H, total), 4.11 (s, 1H), 3.11-2.78(m, 20H), 2.51-2.40 (m, 1H), 2.28-2.25 (m, 1H), 2.10 (s, 1H), 1.77-1.54(m, 11H), 1.31-1.26 (m, 2H); MS (ESI) m/z 611.1 (M+H).

S16-10-76:

¹H NMR (400 MHz, CD₃OD) δ 6.94 (s, 1H), 4.68, 4.65, 4.51, 4.47 (s, 1H,total), 4.33, 4.30, 4.17, 4.13 (s, 1H, total), 4.10 (s, 1H), 3.16-2.82(m, 19H), 2.53-2.41 (m, 1H), 2.38-2.33 (m, 1H), 2.13-2.10 (m, 1H),1.77-1.58 (m, 11H), 1.39-1.30 (m, 2H), 1.28-1.21 (m, 3H); MS (ESI) m/z625.3 (M+H).

S16-10-77:

¹H NMR (400 MHz, CD₃OD) δ 6.97, 6.93 (s, 1H, total), 4.65, 4.62, 4.36,4.33 (s, 1H, total), 4.39 (s, 1H), 4.10 (s, 1H), 3.28-3.31 (m, 4H),3.13-2.80 (m, 15H), 2.53-2.41 (m, 1H), 2.29-2.26 (m, 1H), 1.64-1.62 (m,1H), 1.41-1.34 (m, 3H), 2.24 (t, J=6.8 Hz, 2H), 1.09-1.04 (m, 6H); MS(ESI) m/z 585.1 (M+H).

S16-10-78:

¹H NMR (400 MHz, CD₃OD) δ 7.01 (s, 1H), 4.79, 4.76, 4.65, 4.62 (s, 1H,total), 4.47, 4.43, 4.41, 4.37 (s, 1H, total), 4.13 (s, 1H), 3.53-3.51(m, 1H), 3.19-2.89 (m, 18H), 2.53-2.41 (m, 1H), 2.32-2.29 (m, 1H),1.68-1.63 (m, 1H), 1.31-1.25 (m, 1H), 1.15 (s, 9H), 0.86-0.80 (m, 2H),0.50-0.39 (m, 2H); MS (ESI) m/z 611.1 (M+H).

S16-10-79:

¹H NMR (400 MHz, CD₃OD) δ 6.98 (s, 1H), 4.45-4.42 (m, 1H), 4.31-4.27 (m,1H), 4.12 (s, 1H), 3.12-2.82 (m, 16H), 2.49-2.42 (m, 1H), 2.31-2.28 (m,1H), 1.68-1.62 (m, 1H), 1.40 (d, J=7.2 Hz, 3H), 1.08 (s, 9H); MS (ESI)m/z 571.3 (M+H).

S16-10-80:

¹H NMR (400 MHz, CD₃OD) δ 7.07, 6.97 (s, 1H, total), 4.66 (d, J=11.6 Hz,1H), 4.33 (d, J=13.2 Hz, 1H), 4.15 (s, 1H), 3.53-3.50 (m, 1H), 3.23-2.82(m, 18H), 2.55-2.46 (m, 1H), 2.33-2.30 (m, 1H), 1.71-1.62 (m, 1H), 1.52,1.43 (s, 3H, total), 1.24 (s, 3H), 1.10 (s, 6H), MS (ESI) m/z 585.1(M+H).

S16-10-81:

¹H NMR (400 MHz, CD₃OD) δ 7.01, 6.94 (s, 1H, total), 4.60 (d, J=13.6 Hz,1H), 4.19 (d, J=13.6 Hz, 1H), 4.11 (s, 1H), 3.61-3.59 (m, 1H), 3.19-2.89(m, 17H), 2.55-3.42 (m, 1H), 2.29-2.26 (m, 1H), 1.64-1.59 (m, 1H),1.49-1.41 (m, 4H), 1.30 (t, J=6.8 Hz, 2H), 1.28, 0.95 (s, 9H, total); MS(ESI) m/z 599.2 (M+H).

S16-10-82:

¹H NMR (400 MHz, CD₃OD) δ 7.01, 6.94 (s, 1H, total), 4.63, 4.60, 4.17,4.14 (s, 1H, total), 4.12 (s, 1H), 3.88-3.86 (m, 1H), 3.19-2.90 (m,18H), 2.55-2.42 (m, 1H), 2.31-2.28 (m, 1H), 1.68-1.63 (m, 1H), 1.55-1.52(m, 2H), 1.45-1.41 (m, 1H), 1.22 (s, 6H), 1.06-1.02 (m, 1H), 0.96 (s,3H), 0.82-0.75 (m, 1H), 0.71-0.63 (m, 1H), 0.42-0.36 (m, 1H), 0.25-0.20(m, 1H); MS (ESI) m/z 625.3 (M+H).

S16-10-83:

¹H NMR (400 MHz, CD₃OD) δ 6.84 (s, 1H), 4.46 (d, J=14.0 Hz, 1H), 4.14(d, J=14.0 Hz, 1H), 4.05 (s, 1H), 3.96-3.92 (m, 1H), 3.82-3.77 (m, 1H),3.06-2.84 (m, 16H), 2.43-2.37 (m, 1H), 2.24-2.20 (m, 1H), 1.62-1.53 (m,1H), 1.06 (s, 9H); MS (ESI) m/z 587.1 (M+H)

S16-10-84

¹H NMR (400 MHz, CD₃OD) δ 6.94 (s, 1H), 4.79-4.76 (m, 1H), 4.58-4.52 (m,1H), 4.13 (s, 1H), 4.08-4.05 (m, 1H), 3.99-3.94 (m, 1H), 3.49-3.47 (m,1H), 3.12-2.80 (m, 18H), 2.52-2.48 (m, 1H), 2.30-2.28 (m, 1H), 1.68-1.63(m, 1H), 1.28-1.10 (m, 9H); MS (ESI) m/z 601.1 (M+H).

S16-10-85:

¹H NMR (400 MHz, CD₃OD) δ 7.01, 6.92 (s, 1H total), 4.56-4.54 (m, 1H),4.13 (s, 3H), 3.60-3.48 (m, 2H), 3.21-2.91 (m, 17H), 2.58-2.51 (m, 1H),2.31-2.28 (m, 1H), 1.71-1.61 (m, 1H), 1.29, 1.25 (s, 9H total),1.09-1.07 (m, 3H); MS (ESI) m/z 615.4 (M+H)

S16-10-86:

¹H NMR (400 MHz, CD₃OD) δ 6.93 (s, 1H), 4.32 (d, J=14.0 Hz, 1H), 4.11(d, J=14.0 Hz, 1H), 4.07 (s, 1H), 3.44-3.41 (m, 1H), 3.02-2.77 (m, 15H),2.48-2.37 (m, 1H), 2.25-2.22 (m, 1H), 1.66-1.56 (m, 1H), 1.38-1.36 (m,6H); MS (ESI) m/z 529.0 (M+H).

S16-10-87:

¹H NMR (400 MHz, CD₃OD) δ 6.95 (s, 1H), 4.62-4.56 (m, 1H), 4.28-4.25 (m,1H), 4.10 (s, 1H), 3.08-2.82 (m, 18H), 2.53-2.49 (m, 1H), 2.28-2.23 (m,1H), 1.68-1.62 (m, 1H), 1.48-1.43 (m, 2H), 1.42-1.31 (m, 7H); MS (ESI)m/z 557.1 (M+H).

S16-10-88:

¹H NMR (400 MHz, CD₃OD) δ 6.89 (s, 1H), 4.33-4.29 (m, 1H), 4.12-4.07 (m,1H), 4.04 (s, 1H), 3.05-2.74 (m, 16H), 2.42-2.31 (m, 1H), 2.21-2.18 (m,1H), 1.89-1.81 (m, 1H), 1.59-1.53 (m, 2H), 1.32 (d, J=6.4 Hz, 3H), 0.97(t, J=6.4 Hz, 3H); MS (ESI) m/z 543.1 (M+H).

S16-10-89:

¹H NMR (400 MHz, CD₃OD) δ 6.97, 6.96 (s, 1H, total), 4.68-4.63 (m, 1H),4.42-4.38 (m, 1H), 4.11 (s, 1H), 3.48-3.43 (m, 1H), 3.10-2.80 (m, 18H),2.51-2.45 (m, 1H), 2.31-2.28 (m, 1H), 1.91-1.85 (m, 1H), 1.71-1.60 (m,2H), 1.43-1.43 (m, 3H), 1.09-1.01 (m, 3H) MS (ESI) m/z 557.1 (M+H).

S16-10-90:

¹H NMR (400 MHz, CD₃OD) δ 6.94 (s, 1H), 4.68, 4.64, 4.54, 4.51 (s, 1H,total), 4.34, 4.31, 4.23, 4.20 (s, 1H, total), 4.10 (s, 1H), 3.18-2.83(m, 18H), 2.55-2.42 (m, 1H), 2.37-2.34 (m, 1H), 2.29-2.26 (m, 1H),2.02-1.95 (m, 2H), 1.67 (s, 3H), 1.39-1.28 (m, 6H); MS (ESI) m/z 571.1(M+H).

S16-10-91:

¹H NMR (400 MHz, CD₃OD) δ 7.01 (s, 1H), 4.44 (d, J=13.6 Hz, 1H), 4.20(d, J=13.2 Hz, 1H), 4.14 (s, 1H), 3.21-2.88 (m, 16H), 2.54-2.42 (m, 1H),2.33-2.29 (m, 1H), 2.21-2.13 (m, 1H), 1.68-1.63 (m, 1H), 1.39-1.31 (m,3H), 1.10-1.03 (m, 6H), MS (ESI) m/z 557.1 (M+H).

S16-10-92:

¹H NMR (400 MHz, CD₃OD) δ 7.01, 6.99 (s, 1H, total), 4.70, 4.67, 4.56,4.53 (s, 1H, total), 4.44, 4.41, 4.02, 3.99 (s, 1H, total), 4.17 (s,1H), 3.19-2.86 (m, 19H), 2.53-2.48 (m, 1H), 2.35-2.27 (m, 1H), 2.16-2.12(m, 1H), 1.72-1.62 (m, 1H), 1.47, 1.45, 1.41, 1.40 (s, 3H, total),1.22-1.06 (m, 6H); MS (ESI) m/z 571.3 (M+H).

S16-10-93:

¹H NMR (400 MHz, CD₃OD) δ 7.00, 6.98 (s, 1H, total), 4.69 (t, J=28.8,14.0 Hz, 1H), 4.34, 4.30, 4.14, 4.10 (s, 1H, total), 4.16 (s, 1H),3.52-3.43 (m, 1H), 3.23-2.92 (m, 17H), 2.60-2.50 (m, 1H), 2.34-2.31 (m,1H), 2.28-2.13 (m, 1H), 1.75-1.62 (m, 1H), 1.51, 1.33 (t, J=7.2 Hz, 3H,total), 1.43-1.38 (m, 3H), 1.20, 1.14, 1.05 (d, J=6.4 Hz, 6H, total); MS(ESI) m/z 585.1 (M+H).

S16-10-94:

¹H NMR (400 MHz, CD₃OD) δ 7.03, 7.01 (s, 1H, total), 5.49, 5.45, 4.74,4.70 (s, 1H, total), 4.34, 4.31, 4.17, 4.13 (s, 1H, total), 4.17 (s,1H), 3.21-2.93 (m, 18H), 2.60-2.49 (m, 1H), 2.37-2.33 (m, 1H), 2.28-2.16(m, 1H, total), 1.73-1.68 (m, 1H), 1.49, 1.44 (d, J=6.8 Hz, 3H, total),1.28, 1.22 (d, J=6.4 Hz, 3H, total), 1.09-1.05 (m, 3H), 0.98-0.92 (m,1H), 0.88-0.83 (m, 1H), 0.77-0.54 (m, 1H), 0.55-0.48 (m, 1H), 0.28-0.23(m, 1H); MS (ESI) m/z 611.3 (M+H).

S16-10-95:

¹H NMR (400 MHz, CD₃OD) δ 7.02 (s, 1H), 4.43 (d, J=14.0 Hz, 1H), 4.23(d, J=13.6 Hz, 1H), 4.15 (s, 1H), 3.14-2.87 (m, 16H), 2.48-2.40 (m, 1H),2.34-2.29 (m, 1H), 2.18-2.16 (m, 1H), 1.73-1.53 (m, 1H), 1.35 (d, J=6.8Hz, 3H), 1.07 (d, J=6.8 Hz, 3H), 1.05 (d, J=6.8 Hz, 3H); MS (ESI) m/z557.3 (M+H).

S16-10-96:

¹H NMR (400 MHz, CD₃OD) δ 6.88 (s, 1H), 4.60-4.57 (m, 1H), 4.20-4.16 (m,1H), 4.02 (s, 1H), 2.97-2.58 (m, 19H), 2.52-2.36 (m, 1H), 2.20-2.18 (m,1H), 2.05-1.90 (m, 1H), 1.60-1.48 (m, 1H), 1.33 (d, J=6.4 Hz, 3H), 1.07(d, J=6.4 Hz, 3H), 1.02 (d, J=6.4 Hz, 3H); MS (ESI) m/z 571.1 (M+H)

S16-10-97:

¹H NMR (400 MHz, CD₃OD) δ 6.98 (s, 1H), 4.70, 4.67, 4.28, 4.25 (s, 1H,total), 4.85, 4.46 (s, 1H, total), 4.13 (s, 1H), 3.16-2.83 (m, 18H),2.54-2.45 (m, 1H), 2.32-2.23 (m, 1H), 2.02-1.95 (m, 1H), 1.67-1.64 (m,1H), 1.45-1.33 (m, 3H), 1.28-1.26 (m, 1H), 1.18-1.13 (m, 9H); MS (ESI)m/z 585.3 (M+H).

S16-10-98:

¹H NMR (400 MHz, CD₃OD) δ 6.99, 6.93 (s, 1H, total), 4.63, 4.61, 4.59,4.58 (s, 1H, total), 4.50, 4.47, 4.43, 4.40 (s, 1H, total), 4.11 (s,1H), 3.14-2.85 (m, 18H), 2.56-2.45 (m, 1H), 2.32-2.25 (m, 1H), 2.15-2.08(m, 1H), 1.69-1.60 (m, 1H), 1.41, 1.34 (d, J=8.0 Hz, 3H, total), 1.15(d, J=6.8 Hz, 3H), 1.07 (d, J=7.2 Hz, 3H), 0.83-0.79 (m, 2H), 0.65-0.58(m, 1H), 0.48-0.43 (m, 1H), 0.38-0.21 (m, 1H); MS (ESI) m/z 611.2 (M+H).

S16-10-99:

¹H NMR (400 MHz, CD₃OD) δ 7.05, 7.03 (s, 1H, total), 4.73 (s, 1H), 4.45(s, 1H), 4.14 (s, 1H), 3.10-2.85 (m, 19H), 2.50-2.40 (m, 1H), 2.31-2.28(m, 1H), 1.72-1.63 (m, 1H), 1.00-0.95 (m, 4H); MS (ESI) m/z 541.1 (M+H).

S16-10-100:

¹H NMR (400 MHz, CD₃OD) δ 7.08 (s, 1H), 4.81, 4.77 (s, 1H, total), 4.52,4.48 (s, 1H, total), 4.18 (s, 1H), 3.16-2.90 (m, 18H), 2.57-2.43 (m,1H), 2.36-2.33 (m, 1H), 1.76-1.73 (m, 1H), 1.53 (t, J=7.2 Hz, 3H),1.20-1.03 (m, 3H), 0.95-0.82 (m, 1H); MS (ESI) m/z 555.1 (M+H).

S16-10-101:

¹H NMR (400 MHz, CD₃OD) δ 6.95 (s, 1H), 4.48 (d, J=13.6 Hz, 1H), 4.25(d, J=12.8 Hz, 1H), 4.12 (s, 1H), 3.08-2.80 (m, 15H), 2.48-2.38 (m, 1H),2.28-2.25 (m, 1H), 1.68-1.63 (m, 1H), 1.58 (s, 3H), 1.15 (s, 2H), 0.88(s, 2H); MS (ESI) m/z 541.1 (M+H).

S16-10-102:

¹H NMR (400 MHz, CD₃OD) δ 6.95 (s, 1H), 4.46 (d, J=14 Hz, 1H), 4.14 (s,1H), 4.11 (d, J=14 Hz, 1H), 3.88-3.84 (m, 1H), 3.07-2.45 (m, 15H),2.45-2.27 (m, 6H), 1.99-1.92 (m, 2H), 1.71-1.62 (m, 1H); MS (ESI) m/z541.1 (M+H).

S16-10-103:

¹H NMR (400 MHz, CD₃OD) δ 7.08, 7.04 (s, 1H, total), 4.52, 4.48, 4.32,4.29 (s, 1H, total), 4.11 (s, 1H), 4.24, 4.21, 4.02, 3.99 (s, 1H,total), 3.90-3.86 (m, 1H), 3.10-2.81 (m, 15H), 2.65 (s, 3H), 2.48-2.37(m, 1H), 2.35-2.24 (m, 5H), 1.89-1.81 (m, 2H), 1.68-1.62 (m, 1H); MS(ESI) m/z 555.1 (M+H).

S16-10-104:

¹H NMR (400 MHz, CD₃OD) δ 7.01, 6.97 (s, 1H, total), 4.52, 4.49, 4.45,4.41 (s, 1H, total), 4.12 (s, 1H), 4.20, 4.17, 4.12, 4.09 (s, 1H,total), 4.00-3.97 (m, 1H), 3.18-2.84 (m, 17H), 2.49-2.38 (m, 1H),2.39-2.20 (m, 5H), 1.88-1.82 (m, 2H), 1.68-1.62 (m, 1H), 1.35-1.28 (m,3H); MS (ESI) m/z 569.1 (M+H).

S16-10-105:

¹H NMR (400 MHz, CD₃OD) δ 7.01, 6.99 (s, 1H, total), 4.68, 4.65, 4.52,4.49 (s, 1H, total), 4.35, 4.31, 4.11, 4.08 (s, 1H, total), 4.11 (s,1H), 4.19-4.16 (m, 1H), 3.10-2.85 (m, 17H), 2.50-2.40 (m, 1H), 2.38-2.33(m, 2H), 2.30-2.15 (m, 3H), 1.90-1.78 (m, 2H), 1.68-1.62 (m, 1H),1.15-1.08 (m, 1H), 0.76-0.74 (m, 2H), 0.48-0.42 (m, 2H); MS (ESI) m/z595.1 (M+H).

S16-10-106:

¹H NMR (400 MHz, CD₃OD) δ 6.98 (s, 1H), 4.22, 4.20 (s, 1H, total), 4.13(s, 1H), 4.06, 4.04 (s, 1H, total), 3.03-2.83 (m, 15H), 2.50-2.40 (m,3H), 2.23-2.29 (m, 1H), 2.16-2.14 (m, 2H), 2.04-1.99 (m, 2H), 1.72-1.65(m, 1H), 1.65 (s, 3H); MS (ESI) m/z 555.1 (M+H).

S16-10-107:

¹H NMR (400 MHz, CD₃OD) δ 7.01, 6.97 (s, 1H, total), 4.43, 4.40, 4.22,4.19 (s, 1H, total), 4.17, 4.14, 3.95, 3.92 (s, 1H, total), 4.12 (s,1H), 3.08-2.79 (m, 15H), 2.67, 2.59 (s, 3H, total), 2.47-2.41 (m, 3H),2.28-2.20 (m, 2H), 2.11-2.04 (m, 1H), 1.92-1.88 (m, 2H), 1.64-1.60 (m,1H), 1.60 (s, 3H); MS (ESI) m/z 569.3 (M+H).

S16-10-108:

¹H NMR (400 MHz, CD₃OD) δ 7.05, 7.04, 7.01, 7.00 (s, 1H, total),4.49-4.38 (m, 1H), 4.17-4.12 (m, 2H), 3.22-2.85 (m, 17H), 2.65-2.21 (m,4H), 2.20-2.05 (m, 2H), 1.98-1.89 (m, 2H), 1.68-1.61 (m, 4H), 1.23-1.15(m, 3H); MS (ESI) m/z 583.2 (M+H).

S16-10-109:

¹H NMR (400 MHz, CD₃OD) δ 7.07, 7.05 (s, 1H, total), 4.57, 4.54, 4.48,4.45 (s, 1H, total), 4.23, 4.20, 4.18, 4.15 (s, 1H, total), 4.13 (s,1H), 3.14-2.93 (m, 17H), 2.54-2.51 (m, 2H), 2.45-2.41 (m, 1H), 2.35-2.18(m, 3H), 1.99-1.89 (m, 3H), 1.68-1.65 (m, 4H), 0.95-0.60 (m, 2H),0.40-0.20 (m, 2H); MS (ESI) m/z 609.1 (M+H).

S16-10-110:

¹H NMR (400 MHz, CD₃OD) δ 6.97 (s, 1H), 4.38 (d, J=14.0 Hz, 1H), 4.17(d, J=13.6 Hz, 1H), 4.12 (s, 1H), 3.69-3.62 (m, 1H), 3.06-2.82 (m, 15H),2.49-2.38 (m, 1H), 2.29-2.22 (m, 1H), 2.18-2.04 (m, 2H), 1.85-1.82 (m,2H), 1.78-1.61 (m, 5H); MS (ESI) m/z 555.3 (M+H).

S16-10-111:

¹H NMR (400 MHz, CD₃OD) δ 7.03 (d, J=6.8 Hz, 1H), 4.68 (d, J=13.2 Hz,1H), 4.51-4.39 (m, 1H), 4.16 (s, 1H), 3.84-3.78 (m, 1H), 3.09-2.86 (m,19H), 2.55-2.48 (m, 1H), 2.34-2.30 (m, 2H), 1.91 (s, 5H), 1.77-1.68 (m,3H); MS (ESI) m/z 569.1 (M+H).

S16-10-112:

¹H NMR (400 MHz, CD₃OD) δ 7.00 (m, J=7.6 Hz, 1H), 4.71-4.59 (m, 1H),4.34-4.25 (m, 1H), 4.15 (s, 1H), 3.27-2.87 (m, 18H), 2.56-2.48 (m, 1H),2.34-2.20 (m, 2H), 1.89 (s, 5H), 1.75-1.67 (m, 3H), 1.43-1.37 (m, 3H);MS (ESI) m/z 583.1 (M+H).

S16-10-113:

¹H NMR (400 MHz, CD₃OD) δ 6.97 (s, 1H), 4.40 (d, J=14 Hz, 1H), 4.19 (d,J=13.6 Hz, 1H), 4.11-4.05 (m, 3H), 4.01-3.98 (m, 1H), 3.75-3.71 (m, 1H),3.09-2.80 (m, 16H), 2.49-2.41 (m, 2H), 2.29-2.26 (m, 1H), 2.15-2.09 (m,1H), 1.68-1.63 (m, 1H); MS (ESI) m/z 557.1 (M+H).

S16-10-114:

¹H NMR (400 MHz, CD₃OD) δ 7.48 (s, 1H), 4.65-4.62, 4.49-4.46 (m, 1H,total), 4.33-4.28 (m, 2H), 4.18-4.10 (m, 3H), 3.75-3.68 (m, 1H),3.09-2.82 (m, 19H), 2.50-2.41 (m, 2H), 2.35-2.25 (m, 2H), 1.68-1.63 (m,1H); MS (ESI) m/z 571.1 (M+H).

S16-10-115:

¹H NMR (400 MHz, CD₃OD) δ 6.96 (s, 1H), 4.71-4.55 (m, 1H), 4.28-4.23 (m,2H), 4.19-4.13 (m, 2H), 4.11 (s, 1H), 3.68-3.63 (m, 1H), 3.09-2.81 (m,18H), 2.53-2.14 (m, 4H), 1.68-1.59 (m, 1H), 1.41-1.33 (m, 3H); MS (ESI)m/z 585.1 (M+H).

S16-10-116:

¹H NMR (400 MHz, CD₃OD) δ 6.97 (s, 1H), 4.45, 4.42 (s, 1H, total), 4.22,4.18 (s, 1H, total), 4.13 (s, 1H), 3.93-3.88 (m, 2H), 3.80-3.73 (m, 1H),3.59-3.55 (m, 1H), 3.17-2.83 (m, 17H), 2.69-2.66 (m, 1H), 2.51-2.40 (m,1H), 2.30-2.17 (m, 2H), 1.75-1.60 (m, 2H); MS (ESI) m/z 571.1 (M+H).

S16-10-117:

¹H NMR (400 MHz, CD₃OD) δ 7.25-7.16 (m, 4H), 6.90 (s, 1H), 4.37 (d, J=14Hz, 1H), 4.13-4.04 (m, 2H), 4.04 (s, 1H), 3.61-3.39 (m, 3H), 3.17-2.58(m, 16H), 2.39-2.31 (m, 1H), 2.21-2.18 (m, 1H), 1.61-1.52 (m, 1H); MS(ESI) m/z 603.0 (M+H).

S16-10-118:

¹H NMR (400 MHz, CD₃OD) δ 7.25-7.18 (m, 4H), 6.95, 6.93 (s, 1H, total),4.58, 4.54, 4.45, 4.42 (s, 1H, total), 4.36, 4.33, 4.06, 4.03 (s, 1H,total), 4.28-4.23 (m, 2H), 4.04 (s, 1H), 3.52-3.27 (m, 6H), 2.98-2.71(m, 15H), 2.45-2.38 (m, 1H), 2.21-2.18 (m, 1H), 1.63-1.54 (m, 1H); MS(ESI) m/z 617.1 (M+H)

S16-10-119:

¹H NMR (400 MHz, CD₃OD) δ 6.89 (s, 1H), 4.22 (d, J=14.2 Hz. 1H), 4.03(d, J=14.4 Hz, 1H), 4.01 (s, 1H), 2.93-2.70 (m, 15H), 2.48-2.38 (m, 1H),2.18-2.14 (m, 1H), 1.85-1.69 (m, 8H), 1.56-1.47 (m, 1H), 1.38 (s, 3H);MS (ESI) m/z 569.0 (M+H).

S16-10-120:

¹H NMR (400 MHz, CD₃OD) δ 6.99 (s, 1H), 4.43-4.39 (m, 1H), 4.22-4.19 (m,1H), 4.14 (s, 1H), 3.23-2.91 (m, 9H), 2.96-2.83 (m, 6H), 2.52-2.42 (m,1H), 2.31-2.28 (m, 1H), 2.25-2.15 (m, 2H), 1.93-1.87 (m, 2H), 1.75-1.61(m, 2H), 1.49-1.25 (m, 6H); MS (ESI) m/z 569.3 (M+H).

S16-10-121:

¹H NMR (400 MHz, CD₃OD) δ 6.97, 6.96 (s, 1H total), 4.69, 4.66, 4.41,4.39 (s, 1H total), 4.38, 4.37, 4.04, 4.01 (s, 1H total), 4.11 (s, 1H),3.21-2.73 (m, 19H), 2.54-2.47 (m, 1H), 2.30-2.26 (m, 1H), 2.13-2.10 (m,2H), 2.00-1.92 (m, 1H), 1.76-1.57 (m, 4H), 1.44-1.20 (m, 4H); MS (ESI)m/z 583.4 (M+H).

S16-10-122:

¹H NMR (400 MHz, CD₃OD) δ 6.98 (s, 1H), 4.74, 4.71, 4.57, 4.54 (s, 1H,total), 4.40, 4.37, 4.19, 4.15 (s, 1H, total), 4.15 (s, 1H), 3.50-3.47(m, 1H), 3.26-2.86 (m, 17H), 2.54-2.45 (m, 1H), 2.37-2.32 (m, 1H),2.18-1.95 (m, 4H), 1.85-1.61 (m, 4H), 1.51-1.28 (m, 6H); MS (ESI) m/z597.1 (M+H).

S16-10-123:

¹H NMR (400 MHz, CD₃OD) δ 7.00 (s, 1H), 4.37, 4.34 (s, 1H, total), 4.14,4.11 (s, 1H, total), 4.11 (s, 1H), 3.09-2.82 (m, 15H), 2.48-2.38 (m,1H), 2.30-2.25 (m, 1H), 1.96-1.84 (m, 3H), 1.75-1.54 (m, 8H), 1.47 (s,3H); MS (ESI) m/z 583.1 (M+H).

S16-10-124:

¹H NMR (400 MHz, CD₃OD) δ 7.08, 7.04 (s, 1H, total), 4.79, 4.76, 4.54,4.51 (s, 1H, total), 4.48, 4.45, 4.24, 4.21 (s, 1H, total), 4.60, 4.16(s, 1H, total), 3.27-2.86 (m, 17H), 2.54-2.47 (m, 1H), 2.33-2.30 (m,1H), 1.73-1.66 (m, 1H), 1.60-1.58 (m, 9H), 1.22-1.20 (m, 3H); MS (ESI)m/z 571.1 (M+H).

S16-10-125:

¹H NMR (400 MHz, CD₃OD) δ 7.10, 7.08 (s, 1H, total), 4.85, 4.81, 4.26,4.23 (s, 1H, total), 4.54 (s, 1H), 4.18 (s, 1H), 3.59-3.54 (m, 1H),3.29-3.27 (m, 1H), 3.18-2.89 (m, 15H), 2.54-2.42 (m, 1H), 2.36-2.34 (m,1H), 2.08-2.04 (m, 1H), 1.98-1.92 (m, 1H), 1.70-1.61 (m, 1H), 1.58-1.56(m, 6H), 1.24-1.19 (m, 6H); MS (ESI) m/z 585.4 (M+H).

S16-10-126:

¹H NMR (400 MHz, CD₃OD) δ 7.02 (s, 1H), 4.36 (d, J=13.2 Hz, 1H),4.15-4.11 (d, J=13.2 Hz, 1H), 4.11 (s, 1H), 3.06-2.84 (m, 16H),2.49-4.41 (m, 1H), 2.35-2.27 (m, 1H), 1.82 (d, J=7.2 Hz, 2H), 1.68-1.63(m, 1H), 1.57 (s, 6H), 1.12 (s, 9H); MS (ESI) m/z 599.6 (M+H).

S16-10-127:

¹H NMR (400 MHz, CD₃OD) δ 7.00, 6.98 (s, 1H, total), 4.87, 4.83, 4.62,4.59 (s, 1H, total), 4.16 (s, 1H), 4.24, 4.21, 3.99, 3.96 (s, 1H,total), 3.14-2.71 (m, 18H), 2.52-2.41 (m, 1H), 2.33-2.30 (m, 1H), 2.01(s, 1H), 1.90-1.81 (m, 1H), 1.70 (s, 3H), 1.68-1.66 (m, 1H), 1.65 (s,3H), 1.17 (s, 9H); MS (ESI) m/z 613.1

S16-10-128:

¹H NMR (400 MHz, CD₃OD) δ 7.04, 7.01 (s, 1H, total), 4.78, 4.74 (s, 1H,total), 4.45 (s, 1H), 4.15, 4.10 (s, 1H, total), 3.58-3.51 (m, 1H),3.19-2.87 (m, 16H), 2.53-2.46 (m, 1H), 2.28-2.21 (m, 1H), 1.94-1.90 (m,1H), 1.88-1.83 (m, 1H), 1.69-1.63 (m, 7H), 1.12 (s, 12H), MS (ESI) m/z627.1 (M+H).

S16-10-129:

¹H NMR (400 MHz, CD₃OD) δ 7.00 (s, 1H), 4.43, 4.39 (s, 1H, total), 4.34,4.31 (s, 1H, total), 4.14 (s, 1H), 3.13-2.77 (m, 16H), 2.49-2.40 (m,1H), 2.31-2.28 (m, 1H), 1.67-1.65 (m, 1H), 1.51, 1.49 (s, 3H, total),1.13-1.05 (m, 1H), 0.82-0.76 (m, 2H), 0.61-0.55 (m, 1H), 0.41-0.37 (m,1H), MS (ESI) m/z 555.0 (M+H).

S16-10-130:

¹H NMR (400 MHz, CD₃OD) δ 6.87, 6.85 (s, 1H, total), 4.70, 4.67, 4.41,4.37 (s, 1H, total), 4.27, 4.23, 3.97, 3.94 (s, 1H, total), 4.01 (s,1H), 2.94-2.67 (m, 19H), 2.41-2.32 (m, 1H), 2.19-2.13 (m, 1H), 1.58-1.53(m, 1H), 1.42-1.37 (m, 3H), 1.21-1.09 (m, 1H), 0.75-0.68 (m, 2H),0.63-0.60 (m, 1H), 0.38-0.33 (m, 1H); MS (ESI) m/z 569.3 (M+H).

S16-10-131:

¹H NMR (400 MHz, CD₃OD) δ 6.87, 6.84 (s, 1H, total), 4.75, 4.71, 4.48,4.44 (s, 1H, total), 4.31, 4.28, 4.04, 4.01 (s, 1H, total), 4.02 (s,1H), 2.94-2.75 (m, 18H), 2.48-2.38 (m, 1H), 2.20-2.15 (m, 1H), 1.58-1.53(m, 1H), 1.37 (d, J=6.8 Hz, 3H), 1.35-1.27 (m, 1H), 1.13 (t, J=6.4 Hz,3H), 0.79-0.70 (m, 2H), 0.51-0.40 (m, 2H); MS (ESI) m/z 583.2 (M+H).

S16-10-132:

¹H NMR (400 MHz, CD₃OD) δ 6.97 (s, 1H), 4.64 (d, J=13.2 Hz, 1H), 4.37(d, J=13.2 Hz, 1H), 4.09 (s, 1H), 3.12-2.81 (m, 15H), 2.46-2.42 (m, 1H),2.28-2.24 (m, 1H), 1.67-1.55 (m, 2H), 1.05-1.04 (m, 2H), 0.84-0.82 (m,2H), 0.75-0.73 (m, 2H), 0.42-0.39 (m, 2H); MS (ESI) m/z 567.0 (M+H).

S16-10-133:

¹H NMR (400 MHz, CD₃OD) δ 7.00 (s, 1H), 4.74, 4.71 (s, 1H, total) 4.54,4.51 (s, 1H, total), 4.10 (s, 1H), 3.09-2.83 (m, 18H), 2.55-2.46 (m,1H), 2.29-2.26 (m, 1H), 1.67-1.64 (m, 2H), 1.15-1.00 (m, 2H), 0.97-0.83(m, 2H), 0.79-0.77 (m, 2H), 0.42-10.37 (m, 2H); MS (ESI) m/z 581.1(M+H).

S16-10-134:

¹H NMR (400 MHz, CD₃OD) δ 7.07, 7.04 (s, 1H, total), 4.94, 4.91, 4.87,4.84 (s, 1H, total), 4.67, 4.64, 4.55, 4.52 (s, 1H, total), 4.16 (s,1H), 3.05-2.88 (m, 17H), 2.60-2.52 (m, 1H), 2.35-2.31 (m, 1H), 1.72-1.65(m, 2H), 1.44 (t, J=14.4, 7.2 Hz, 3H), 1.11-0.75 (m, 6H), 0.51-0.33 (m,2H); MS (ESI) m/z 595.2

S16-10-135:

¹H NMR (400 MHz, CD₃OD) δ 6.98 (d, J=7.6 Hz, 1H), 4.36-4.32 (m, 1H),4.17-4.12 (m, 2H), 3.11-2.82 (m, 16H), 2.67-2.63 (m, 1H), 2.48-2.26 (m,3H), 2.18-2.11 (m, 1H), 1.87-1.42 (m, 7H), 1.21-1.13 (m, 1H); MS (ESI)m/z 581.4 (M+H).

S16-10-136:

¹H NMR (400 MHz, CD₃OD) δ 6.98 (s, 1H), 4.44, 4.41 (s, 1H, total), 4.25,4.21 (s, 1H, total), 4.13 (s, 1H), 3.47-3.41 (m, 1H), 3.12-2.83 (m,15H), 2.50-2.47 (m, 2H), 2.32-2.25 (m, 1H), 1.95-1.81 (m, 2H), 1.66-1.60(m, 3H), 1.45-1.41 (m, 1H), 1.32-1.29 (m, 1H), 1.04 (s, 3H), 0.95, 0.92(s, 6H, total); MS (ESI) m/z 623.1 (M+H).

S16-10-137:

¹H NMR (400 MHz, CD₃OD) δ 6.84 (s, 1H), 4.74, 4.71, 4.54, 4.50 (s, 1H,total), 4.13, 4.09, 3.97, 3.94 (s, 1H, total), 4.00 (s, 1H), 3.55-3.52(m, 1H), 3.01-2.55 (m, 18H), 2.55-2.41 (m, 2H), 2.18-2.13 (m, 1H),1.92-1.85 (m, 1H), 1.75-1.68 (m, 2H), 1.61-1.50 (m, 2H), 1.39-1.25 (m,2H), 1.17, 0.95 (s, 3H, total), 0.88 (d, J=5.6 Hz, 6H); MS (ESI) m/z637.3 (M+H).

S16-10-138:

¹H NMR (400 MHz, CD₃OD) δ 7.00 (s, 1H), 4.36 (d, J=12.8 Hz, 1H),4.13-4.10 (m, 2H), 3.06-2.82 (m, 15H), 2.50-2.38 (m, 1H), 2.29-2.26 (m,4H), 2.02-1.94 (m, 6H), 1.86-1.72 (m, 6H), 1.68-1.58 (m, 1H); MS (ESI)m/z 621.2 (M+H).

S16-10-139:

¹H NMR (400 MHz, CD₃OD) δ 6.86 (s, 1H), 4.32-4.29 (m, 1H), 4.09-4.05 (m,2H)

(m, 17H), 2.39-2.32 (m, 1H), 2.21-2.18 (m, 1H), 1.69-1.52 (m, 3H)

(m, 4H), 0.89-0.86 (m, 3H); MS (ESI) m/z 557.1 (M+H)

S16-10-140:

¹H NMR (400 MHz, CD₃OD) δ 6.94 (s, 1H), 4.41, 4.38 (s, 1H, total), 4.18,4.15 (s, 1H, total), 4.12 (s, 1H), 3.11-2.81 (m, 17H), 2.51-2.44 (m,2H), 2.30-2.23 (m, 1H), 2.12-1.95 (m, 5H), 1.70-1.55 (m, 2H), 1.33 (d,J=6.8 Hz, 1H), 1.25 (s, 3H), 1.05 (s, 1H), 1.02 (s, 3H); MS (ESI) m/z623.2 (M+H).

S16-10-141:

¹H NMR (400 MHz, CD₃OD) δ 6.99 (s, 1H), 4.70, 4.67 (s, 1H, total), 4.41,4.14, 4.11 (s, 1H, total), 4.11 (s, 1H), 3.19-2.81 (m, 20H), 2.50-2.45(m, 2H), 2.29-2.25 (m, 1H), 2.19-2.11 (m, 1H), 2.01-1.92 (m, 5H),1.70-1.51 (m, 2H), 1.26-1.18 (m, 3H), 1.09-1.02 (m, 2H), 0.91 (s, 1H),0.80 (s, 1H); MS (ESI) m/z 637.1 (M+H).

S16-10-142:

¹H NMR (400 MHz, CD₃OD) δ 6.98, 6.96 (s, 1H, total), 4.64, 4.60, 4.55,4.51 (s, 1H, total), 4.29, 4.46, 4.35, 4.22 (s, 1H, total), 4.11 (s,1H), 3.25-2.82 (m, 19H), 2.59-2.53 (m, 1H), 2.52-2.43 (m, 2H), 2.30-2.23(m, 1H), 2.19-2.10 (m, 1H), 2.08-1.92 (m, 5H), 1.69-1.50 (m, 2H),1.29-1.18 (m, 4H), 1.09-1.01 (m, 3H), 0.91 (s, 1H), 0.85 (s, 1H); MS(ESI) m/z 651.2 (M+H).

S16-10-143:

¹H NMR (400 MHz, CD₃OD) δ 6.95-6.85 (m, 1H), 4.65-4.15 (m, 4H), 4.10 (s,1H), 4.04-3.96 (m, 1H), 3.87-3.80 (m, 1H), 3.05-2.81 (m, 15H), 2.47-2.39(m, 1H), 2.28-2.25 (m, 1H), 1.69-1.63 (m, 1H), 1.35-1.34 (m, 2H),1.28-1.26 (m, 2H), 1.21-1.18 (m, 1H); MS (ESI) m/z 541.5 (M+H).

S16-10-144:

¹H NMR (400 MHz, CD₃OD) δ 6.86 (d, J=14.4 Hz, 1H), 4.69-4.53 (m, 2H),4.40-4.24 (m, 4H), 4.12 (s, 1H), 4.04-3.98 (m, 2H), 3.36 (s, 3H),3.09-2.82 (m, 15H), 2.48-2.25 (m, 2H), 1.64 (ddd, J=13.6, 11.2, 13.2 Hz,1H); MS (ESI) m/z 557.0 (M+H).

S16-10-145:

¹H NMR (400 MHz, CD₃OD) δ 7.04 (s, 1H), 4.62-4.59 (m, 1H), 4.36-4.31 (m,1H), 4.14 (s, 1H), 3.68-3.63 (m, 2H), 3.23-3.17 (m, 2H), 3.14-2.99 (m,9H), 2.89-2.83 (m, 6H), 2.54-2.44 (m, 1H), 2.37-2.28 (m, 1H), 2.23-2.18(m, 2H), 2.13-2.07 (m, 2H), 1.71-1.62 (m, 1H); MS (ESI) m/z 541.3 (M+H).

S16-10-146:

¹H NMR (400 MHz, CD₃OD) δ 6.94 (s, 1H), 4.38-4.35 (m, 2H), 4.03 (s, 1H),3.59-3.52 (m, 1H), 3.47-3.40 (m, 2H), 3.05-2.74 (m, 16H), 2.45-2.32 (m,1H), 2.34-2.28 (m, 1H), 2.21-2.17 (m, 1H), 2.09-2.05 (m, 1H), 2.00-1.95(m, 1H), 1.78-1.70 (m, 1H), 1.60-1.57 (m, 1H), 1.43, 1.42 (s, 3H,total); MS (ESI) m/z 555.0 (M+H).

S16-10-147:

¹H NMR (400 MHz, CD₃OD) δ 6.98 (s, 1H), 4.74, 4.71, 4.12, 4.09 (s, 1H,total), 4.10 (s, 1H), 3.65-3.53 (m, 2H), 3.08-2.81 (m, 17H), 2.52-2.40(m, 1H), 2.41-2.35 (m, 1H), 2.28-2.23 (m, 1H), 2.18-2.10 (m, 1H),2.08-2.03 (m, 1H), 1.74-1.68 (m, 1H), 1.68-1.60 (m, 1H), 1.49 (d, J=6.4Hz, 3H); MS (ESI) m/z 555.1 (M+H).

S16-10-148:

¹H NMR (400 MHz, CD₃OD) δ 6.97 (s, 1H), 4.72, 4.68 (s, 1H, total), 4.21(s, 1H), 4.12, 4.09 (s, 1H, total), 3.87-3.80 (m, 1H), 3.45-3.41 (m,7H), 3.16-3.01 (m, 10H), 2.75-2.69 (m, 2H), 2.49-2.44 (m, 1H), 2.40-2.38(m, 1H), 2.18-2.07 (m, 2H), 1.73-1.65 (m, 1H); MS (ESI) m/z 609.0 (M+H).

S16-10-149:

¹H NMR (400 MHz, CD₃OD) δ 6.86 (s, 1H), 4.48 (d, J=12.8 Hz, 1H), 4.28(d, J=13.2 Hz, 1H), 4.02 (s, 1H), 3.77-3.42 (m, 5H), 3.36 (s, 3H),3.13-2.70 (m, 15H), 2.39-2.32 (m, 1H). 2.24-2.19 (m, 2H), 2.16-2.07 (m,1H), 2.05-1.87 (m, 2H), 1.61-1.49 (m, 1H); MS (ESI) m/z 585.0 (M+H).

S16-10-150:

¹H NMR (400 MHz, CD₃OD) δ 6.83 (s, 1H), 4.03 (s, 2H), 3.83-3.64 (m, 2H),3.63-3.53 (m, 2H), 3.51-3.46 (m, 1H), 3.43 (s, 3H), 3.41-3.35 (m, 1H),3.12-2.63 (m, 15H), 2.50-2.35 (m, 1H), 2.34-2.14 (m, 2H), 2.13-1.83 (m,3H), 1.68-1.43 (m, 1H); MS (ESI) m/z 585.0 (M+H).

S16-10-151:

¹H NMR (400 MHz, CD₃OD) δ 6.93 (s, 1H), 5.46, 5.33 (s, 1H, total), 4.58(d, J=14.2 Hz, 1H), 4.34 (d, J=14.2 Hz, 1H), 4.04 (s, 1H), 3.85-3.61 (m,2H), 3.40-3.39 (m, 1H), 3.01-2.75 (m, 16H), 2.43-2.18 (m, 4H), 1.59-1.56(m, 1H), MS (ESI) m/z 559.3 (M+H).

S16-10-152:

¹H NMR (400 MHz, CD₃OD) δ 7.00 (s, 1H), 5.55, 5.40 (s, 1H, total), 4.63,4.60 (s, 1H, total), 4.39-4.31 (m, 1H), 4.10 (s, 1H), 3.89-3.76 (m, 2H),3.08-2.82 (m, 17H), 2.51-2.35 (m, 3H), 2.32-2.23 (m, 1H), 1.69-1.57 (m,1H); MS (ESI) m/z 559.2 (M+H)

S16-10-153:

¹H NMR (400 MHz, CD₃OD) δ 6.99 (s, 1H), 4.64, 4.61 (s, 1H, total), 4.29,4.26 (s, 1H, total), 4.13 (s, 1H), 3.7 (t, J=23.2, 11.6 Hz, 2H),3.59-3.51 (m, 2H), 3.15-2.96 (m, 15H), 2.69-2.60 (m, 2H), 2.55-2.42 (m,1H), 2.33-2.30 (m, 1H), 1.66-1.63 (m, 1H); MS (ESI) m/z 577.0 (M+H).

S16-10-154:

¹H NMR (400 MHz, CD₃OD) δ 7.03, 7.02 (s, 1H, total), 4.63-4.55 (m, 1H),4.33 (t, J=28.8, 14.4 Hz, 1H), 4.12 (s, 1H), 3.69-3.66 (m, 1H),3.42-3.39 (m, 1H), 3.05-2.83 (m, 17H), 2.51-2.40 (m, 1H), 2.29-2.26 (m,1H), 2.05-2.01 (m, 1H), 1.99-1.92 (m, 1H), 1.66-1.56 (m, 5H), 0.92-0.86(m, 6H); MS (ESI) m/z 597.1 (M+H).

S16-10-155:

¹H NMR (400 MHz, CD₃OD) δ 7.00 (s, 1H), 4.63, 4.60 (s, 1H, total), 4.32,4.29 (s, 1H, total), 4.11 (s, 1H), 3.74-3.71 (m, 2H), 3.06-2.86 (m,15H), 2.49-3.38 (m, 1H), 2.32-2.26 (m, 3H), 1.83-1.81 (m, 2H), 1.69-1.60(m, 1H), 1.39, 1.38 (s, 3H, total), 1.31, 1.30 (s, 3H, total); MS (ESI)m/z 569.1 (M+H).

S16-10-156:

¹H NMR (400 MHz, CD₃OD) δ 6.97 (s, 1H), 4.48-4.22 (m, 2H), 4.11 (s, 1H),3.92-3.81 (m, 1H), 3.52-3.42 (m, 1H), 3.22-2.68 (m, 17H), 2.63-2.51 (m,1H), 2.50-2.41 (m, 1H), 2.31-2.22 (m, 1H), 2.21-2.10 (m, 1H), 1.94 (s,3H), 1.64-1.58 (m, 1H); MS (ESI) m/z 598.2 (M+H).

S16-10-157:

¹H NMR (400 MHz, CD₃OD) δ 6.91 (s, 1H), 4.73-4.69 (m, 1H), 4.22 (s, 1H),4.10 (s, 1H), 3.79-3.74 (m, 1H), 3.50-3.40 (m, 1H), 3.20-2.88 (m, 17H),2.61-2.41 (m, 2H), 2.31-2.22 (m, 1H), 2.19-2.08 (m, 1H), 1.95 (s, 3H),1.66-1.57 (m, 1H); MS (ESI) m/z 598.2 (M+H).

S16-10-158:

¹H NMR (400 MHz, CD₃OD) δ 7.02, 7.00 (s, 1H, total), 4.55 (t, J=22.8,13.2 Hz, 1H), 4.32, 4.29, 4.24, 4.21 (s, 1H, total), 4.12 (s, 1H),3.45-3.41 (m, 1H), 3.20-3.15 (m, 1H), 3.10-2.75 (m, 19H), 2.49-2.41 (m,1H), 2.28-2.23 (m, 1H), 1.85-1.53 (m, 7H); MS (ESI) m/z 581.1 (M+H).

S16-10-159:

¹H NMR (400 MHz, CD₃OD) δ 6.95 (s, 1H), 4.58-4.53 (m, 1H), 4.32-4.29 (m,1H), 4.03 (s, 1H), 3.58-3.39 (m, 3H), 3.12-2.75 (m, 16H), 2.57-2.33 (m,3H), 2.20-2.17 (m, 1H), 1.65-1.33 (m, 9H); MS (ESI) m/z 595.2 (M+H).

S16-10-160:

¹H NMR (400 MHz, CD₃OD) δ 7.32 (s, 4H), 6.98 (s, 1H), 4.76-4.43 (m, 6H),4.05 (s, 1H), 3.01-2.73 (m, 15H), 2.44-2.36 (m, 1H), 2.21-2.18 (m, 1H),1.62-1.53 (m, 1H); MS (ESI) m/z 589.0 (M+H).

S16-10-161:

¹H NMR (400 MHz, CD₃OD) δ 7.06 (s, 1H), 4.54-4.47 (m, 1H), 4.29-4.26 (m,1H), 4.14 (s, 1H), 3.51-3.44 (m, 2H), 3.10-2.98 (m, 11H), 2.89-2.83 (m,6H), 2.51-2.43 (m, 1H), 2.31-2.27 (m, 1H), 1.97-1.92 (m, 2H), 1.88-1.81(m, 3H), 1.69-1.52 (m, 2H); MS (ESI) m/z 555.2 (M+H).

S16-10-162:

¹H NMR (400 MHz, CD₃OD) δ 7.04, 7.03 (s, 1H, total), 4.50 (d, J=13.2 Hz,1H), 4.25 (d, J=13.2 Hz, 1H), 4.11 (s, 1H), 3.51-3.42 (m, 2H), 3.20-2.81(m, 17H), 2.49-2.41 (m, 1H), 2.29-2.25 (m, 1H), 1.93-1.90 (m, 2H),1.73-1.62 (m, 2H), 1.60-1.42 (m, 2H), 1.01 (d, J=6.4 Hz, 3H); MS (ESI)m/z 569.0 (M+H)

S16-10-163:

¹H NMR (400 MHz, CD₃OD) δ 6.94, 6.93 (s, 1H, total), 4.40 (d, J=12.8 Hz,1H), 4.16 (d, J=13.2 Hz, 1H), 3.98 (s, 1H), 3.52-3.49 (m, 1H), 3.42-3.39(m, 1H), 3.07-2.67 (m, 18H), 2.36-2.28 (m, 1H), 2.15-2.12 (m, 1H), 2.02(m, 2H), 1.77-1.74 (m, 2H), 1.55-1.49 (m, 1H); MS (ESI) m/z 623.0 (M+H).

S16-10-164:

¹H NMR (400 MHz, CD₃OD) δ 7.04 (s, 1H), 4.49 (d, J=13.2 Hz, 1H), 4.24(d, J=13.2 Hz, 1H), 4.12 (s, 1H), 3.54-3.47 (m, 2H), 3.05-2.80 (m, 17H),2.43-2.38 (m, 1H), 2.28-2.25 (m, 1H), 2.01-1.96 (m, 2H), 1.67-1.64 (m,1H), 1.55-1.41 (m, 4H), 0.99 (d, J=6.8 Hz, 6H); MS (ESI) m/z 597.3(M+H).

S16-10-165:

¹H NMR (400 MHz, CD₃OD) δ 7.06 (s, 1H), 4.52, 4.49 (s, 1H, total), 4.28,4.24 (s, 1H, total), 4.13 (s, 1H), 3.59-3.49 (m, 2H), 3.41-3.35 (m, 1H),3.07-2.82 (m, 16H), 2.50-2.41 (m, 1H), 2.30-2.27 (m, 1H), 2.02-1.98 (m,2H), 1.68-1.60 (m, 3H), 1.46-1.40 (m, 1H), 0.98 (s, 9H); MS (ESI) m/z611.1 (M+H).

S16-10-166:

¹H NMR (400 MHz, CD₃OD) δ 6.95 (s, 1H), 4.42 (d, J=13.2 Hz, 1H), 4.19(d, J=14.0 Hz, 1H), 4.03 (s, 1H), 3.45-3.35 (m, 2H), 3.05-2.70 (m, 17H),2.40-2.29 (m, 1H), 2.20-2.13 (m, 1H), 1.93-1.85 (m, 2H), 1.59-1.50 (m,2H), 1.39-1.18 (m, 6H), 0.88-0.79 (m, 3H); MS (ESI) m/z 597.1 (M+H).

S16-10-167:

¹H NMR (400 MHz, CD₃OD) δ 6.93, 6.89 (s, 1H, total), 4.52, 4.48, 4.46,4.41 (s, 1H, total), 4.27, 4.24, 4.18, 4.14 (s, 1H, total), 4.01 (s,1H), 2.98-2.70 (m, 18H), 2.43-2.38 (m, 1H), 2.18-2.13 (m, 1H), 1.95-1.93(m, 1H), 1.80-1.74 (m, 2H), 1.65-1.58 (m, 4H), 1.45 (d, J=6.4 Hz, 2H),1.39 (d, J=6.8 Hz, 1H); MS (ESI) m/z 569.1 (M+H).

S16-10-168:

¹H NMR (400 MHz, CD₃OD) δ 7.23-7.17 (m, 5H), 7.02 (s, 1H), 4.51-4.47 (m,1H), 4.26-4.22 (m, 1H), 4.03 (s, 1H), 3.58-3.47 (m, 2H), 3.15-2.75 (m,17H), 2.59-2.55 (m, 1H), 2.42-2.35 (m, 1H), 2.21-2.18 (m, 1H), 2.01-1.94(m, 3H), 1.62-1.52 (m, 1H), 1.20-1.18 (m, 1H); MS (ESI) m/z 631.1 (M+H).

S16-10-169:

¹H NMR (400 MHz, CD₃OD) δ 7.05, 7.04 (s, 1H, total), 4.56-4.55 (m, 1H),4.30-4.23 (m, 1H), 4.10 (s, 1H), 4.07, 3.87 (m, 1H, total), 3.57-3.45(m, 1H), 3.38-3.33 (m, 2H), 3.19-2.81 (m, 15H), 2.52-2.40 (m, 1H),2.29-2.23 (m, 1H), 2.19-2.13 (m, 1H), 2.07-2.85 (m, 2H), 1.79-1.57 (m,2H); MS (ESI) m/z 571.0 (M+H).

S16-10-170:

¹H NMR (400 MHz, CD₃OD) δ 7.05, 7.03 (s, 1H total), 4.53 (d, J=13.2 Hz,1H), 4.28 (d, J=13.2 Hz, 1H), 4.11 (s, 1H), 3.40-3.37 (m, 2H), 3.16-2.81(m, 17H), 2.51-2.43 (m, 1H), 2.28-2.25 (m, 1H), 1.90-1.79 (m, 4H),1.71-1.61 (m, 1H), 1.29 (s, 3H); MS (ESI) m/z 585.1 (M+H).

S16-10-171:

¹H NMR (400 MHz, CD₃OD) δ 7.09 (s, 1H), 4.55-4.51 (m, 1H), 4.36-4.28 (m,1H), 4.14 (s, 1H), 3.64 (s, 1H), 3.58-3.51 (m, 1H), 3.38 (s, 3H),3.18-2.84 (m, 15H), 2.51-2.42 (m, 1H), 2.31-2.28 (m, 2H), 2.18-2.13 (m,1H), 2.05-1.95 (m, 2H), 1.78-1.62 (m, 2H); MS (ESI) m/z 585.1 (M+H).

S16-10-172:

¹H NMR (400 MHz, CD₃OD) δ 6.95 (s, 1H), 4.44-4.40 (m, 1H), 4.19-4.15 (m,1H), 4.03 (s, 1H), 3.47-3.34 (m, 2H), 3.23 (s, 3H), 3.01-2.71 (m, 19H),2.41-2.33 (m, 1H), 2.20-2.17 (m, 1H), 1.92-1.81 (m, 3H), 1.61-1.44 (m,3H); MS (ESI) m/z 599.3 (M+H).

S16-10-180:

¹H NMR (400 MHz, CD₃OD) δ 6.93 (s, 1H), 4.60 (d, J=13.6 Hz, 1H), 4.22(d, J=13.6 Hz, 1H), 4.09 (s, 1H), 3.24-2.86 (m, 19H), 2.52-2.42 (m, 1H),2.30-2.20 (m, 1H), 1.71-1.55 (m, 4H), 1.41-1.31 (m, 3H), 1.03-0.99 (m,6H); MS (ESI) m/z 571.2 (M+H).

S16-10-174:

¹H NMR (400 MHz, CD₃OD) δ 7.03 (s, 1H), 4.51 (d, J=13.2 Hz, 1H), 4.25(d, J=13.2 Hz, 1H), 4.11 (s, 1H), 3.40-3.37 (m, 2H), 3.05-2.80 (m, 17H),2.68-2.57 (m, 2H), 2.47-2.43 (m, 1H), 2.28-2.25 (m, 1H), 1.89-1.85 (m,2H), 1.71-1.61 (m, 1H), 0.99 (d, J=3.6 Hz, 3H), 0.98 (d, J=3.6 Hz, 3H);MS (ESI) m/z 583.3

S16-10-175:

¹H NMR (400 MHz, CD₃OD) δ 7.06 (s, 1H), 4.87 (d, J=20.0 Hz, 1H), 4.17(d, J=13.6 Hz, 1H), 4.13-4.11 (m, 2H), 4.09 (s, 1H), 3.09-2.80 (m, 15H),2.51-2.40 (m, 1H), 2.31-2.23 (m, 3H), 2.18-2.10 (m, 2H), 1.92-1.85 (m,4H), 1.58-1.53 (m, 1H); MS (ESI) m/z 567.1 (M+H).

S16-10-176:

¹H NMR (400 MHz, CD₃OD) δ 7.07 (s, 1H), 4.56 (d, J=13.2 Hz, 1H), 4.30(d, J=13.2 Hz, 1H), 4.11 (s, 1H), 4.05-4.00 (m, 2H), 3.90-3.76 (m, 2H),3.42-3.30 (m, 2H), 3.24-3.16 (m, 2H), 3.07-2.84 (m, 15H), 2.52-2.41 (m,1H), 2.29-2.25 (m, 1H), 1.68-1.58 (m, 1H); MS (ESI) m/z 557.1 (M+H).

S16-10-177:

¹H NMR (400 MHz, CD₃OD) δ 7.03 (s, 1H), 4.61, 4.58 (s, 1H, total), 4.33,4.30 (s, 1H, total), 4.13 (s, 1H), 3.53-3.49 (m, 2H), 3.29-3.26 (m, 2H),3.09-2.85 (m, 15H), 2.49-2.41 (m, 1H), 2.32-2.27 (m, 1H), 2.09-1.95 (m,2H), 1.95-1.83 (m, 2H), 1.68-1.65 (m, 4H), 1.65-1.60 (m, 1H); MS (ESI)m/z 569 (M+H).

S16-10-178:

¹H NMR (400 MHz, CD₃OD) δ 6.97 (s, 1H), 4.73-4.70 (m, 2H), 4.10 (s, 1H),3.52-3.43 (m, 2H), 3.09-2.72 (m, 16H), 2.47-2.33 (m, 2H), 2.29-2.21 (m,1H), 2.17-1.98 (m, 3H), 1.86-1.75 (m, 1H), 1.63-1.49 (m, 2H), 1.05 (t,J=7.2 Hz, 3H); MS (ESI) m/z 569.1 (M+H).

S16-10-179:

¹H NMR (400 MHz, CD₃OD) δ 7.02 (s, 1H), 4.51, 4.49 (s, 1H, total), 4.44,4.41 (s, 1H, total), 4.13 (s, 1H), 3.55-3.49 (m, 2H), 3.06-2.81 (m,16H), 2.46-2.41 (m, 2H), 2.30-2.25 (m, 1H), 2.19-2.01 (m, 3H), 1.85-1.79(m, 1H), 1.70-1.6 (m, 1H), 1.02 (t, J=7.2 Hz, 3H); MS (ESI) m/z 569.1(M+H).

Example 17 Synthesis of Compounds Via Scheme 17

The following compounds were prepared according to Scheme 17.

n-BuLi (5.0 mL, 1.62 M/hexanes, 8.12 mmol, 1.3 equiv) was added dropwiseto a THF solution (30 mL) of S15-5 (2.0 g, 6.24 mmol, 1.0 equiv) at−100° C. The reaction was stirred at −100° C. for 1 min. DMF (2.0 mL,25.00 mmol, 4.0 equiv) was added. The reaction was allowed to warm to−78° C. and stirred at −78° C. for 1 h. The reaction mixture was furtherwarmed to 0° C. and quenched by saturated aqueous NH₄Cl. The resultingmixture was extracted with EtOAc. The combined EtOAc extracts were dried(sodium sulfate) and concentrated to give crude S17-1.

NaBH₄ (0.28 g, 7.40 mmol, 1.2 equiv) was added to a solution of crudeS17-1 (6.24 mmol, 1.0 equiv) in MeOH (15 mL) at 0° C. The reaction wasstirred at 0° C. for 30 min and quenched by H₂O. The resulting mixturewas extracted with EtOAc. The combined EtOAc extracts were dried (sodiumsulfate) and concentrated to give crude S17-2.

N-Bromosuccinimide (1.32 g, 7.44 mmol, 1.2 equiv) was added to asolution of crude S17-2 (6.24 mmol, 1.0 equiv) in dichloromethane (20mL). The reaction was stirred at 25° C. for 2 hrs. Saturated aqueousNa₂SO₃ was added to the reaction. The resulting mixture was extractedwith dichloromethane. The combined dichloromethane extracts were dried(sodium sulfate) and concentrated to give the crude S17-3.

BBr₃ (13.4 mL, 1.0 M/dichloromethane, 13.40 mmol, 2.0 equiv) was addedto a solution of S17-3 dichloromethane (20 mL) at −78° C. The reactionwas stirred from −78° C. to 25° C. for 1.5 hrs, quenched by saturatedaqueous NaHCO₃ and concentrated under reduced pressure to remove most ofthe dichloromethane. EtOAc and H₂O were added to the residue. Theaqueous layer was extracted with EtOAc. The combined EtOAc extracts weredried (sodium sulfate) and concentrated to yield crude phenol. Potassiumcarbonate (1.7 g, 12.40 mmol, 2.0 equiv) and benzylbromide (1.5 mL,12.40 mmol, 2.0 equiv) were added to a solution of the above crudephenol in acetone at 25° C. The reaction was stirred at 25° C. for 12hrs. The reaction mixture was concentrated and the residue wasredissolved in H₂O and EtOAc. The aqueous layer was extracted withEtOAc. The combined organic layers were dried (sodium sulfate) andconcentrated to give crude S17-4. Flash chromatography on silica gel(10:1 to 3:1 hexanes/EtOAc) yielded 1.97 g of compound S-17-4 (72% for 5steps).

Dess-Marlin periodinane (0.18 g, 0.42 mmol, 1.2 equiv) was added to asolution of S17-4 (0.15 g, 0.35 mmol, 1.0 equiv) in dichloromethane (2mL) at 25° C. The reaction was stirred at 25° C. for 30 min and dilutedwith H₂O. The resulting mixture was extracted with dichloromethane. Thecombined dichloromethane extracts were dried (sodium sulfate) andconcentrated to give crude S17-5.

4,4-Dimethylpiperidine hydrochloride (0.11 g, 0.70 mmol, 2.0 equiv) andEt₃N (96 μL, 0.70 mmol, 2.0 equiv) were added to a solution of crudeS17-5 (0.35 mmol, 1.0 equiv) in dichloromethane at 25° C. The reactionwas stirred at 25° C. for 15 min. Na(OAc)₃BH (0.22 g, 1.05 mmol, 3.0equiv) and HOAc (0.1 mL) were added to the reaction. The reaction wasstirred at 25° C. for 1 h and quenched by H₂O. The resulting mixture wasextracted with dichloromethane. The combined dichloromethane extractswere dried (sodium sulfate) and concentrated under reduced pressure.Flash chromatography on silica gel (10:1 to 4:1 hexanes/EtOAc) yielded95 mg of compound S17-6-1 (52% for 2 steps).

n-BuLi (0.55 mL, 1.6 M/hexanes, 0.88 mmol, 1.4 equiv) was added dropwiseto a solution of S17-6-1 (0.33 g, 0.63 mmol, 1.0 equiv) in THF (2 mL) at−100° C. The reaction was stirred at −100° C. for 1 min. TsCN (0.36 g,1.89 mmol, 3.0 equiv) was added to the reaction mixture. The reactionwas allowed to warm to −78° C. and stirred at −78° C. for 1 h. Thereaction mixture was further warmed to 0° C. and quenched by saturatedaqueous NH₄Cl. The resulting mixture was extracted with EtOAc. Thecombined EtOAc extracts were dried (sodium sulfate) and concentratedunder reduced pressure. Flash chromatography on silica gel (4:1hexanes/EtOAc) yielded 28 mg of compound S17-7-1 (10%).

LHMDS (0.24 mL, 1.0 M/THF, 0.24 mmol, 4.0 equiv) was added to a solutionof S17-7-1 (28 mg, 0.060 mmol, 1.2 equiv), TMEDA (54 μL, 0.36 mmol, 7.2equiv) and enone S1-9 (23 mg, 0.050 mmol, 1.0 equiv) in THF (1 mL) at−78° C. The reaction was stirred at −78° C. for 30 min, allowed to warmto 25° C. over 1 h. quenched by saturated NH₄Cl solution, and extractedwith EtOAc. The combined EtOAc extracts were dried (sodium sulfate) andconcentrated under reduced pressure. The crude product was purified bypreparative reverse phase HPLC on a Waters Autopurification system usinga Sunfire Prep C18 OBD column [5 μm, 19×50 mm; flow rate, 20 mL/min;Solvent A: H₂O with 0.1% HCO₂H; Solvent B: CH₃CN with 0.1% HCO₂H;injection volume: 4.0 mL (CH₃CN); gradient: 50→100% B over 15 min;mass-directed fraction collection]. Fractions containing the desiredproduct were collected and concentrated at 25° C. to remove most of theacetonitrile. The resulting aqueous solution was extracted with EtOAc.The combined EtOAc extracts were dried (sodium sulfate) and concentratedto give 8 mg of S17-8-1 (16%).

Aqueous HF (0.3 mL, 48-50%) was added to a solution of S17-8-1 (8 mg,0.0093 mmol) in acetonitrile (2 mL) in a polypropylene tube at 25° C.The reaction was stirred at 25° C. for 18 hrs. The resulting mixture waspoured into an aqueous solution of K₂HPO₄ (2 g, dissolved in 15 mLwater) and extracted with EtOAc. The combined EtOAc extracts were dried(sodium sulfate) and concentrated to yield the crude desilylatedintermediate.

Pd—C (8 mg, 10 wt %) was added to a solution of the above crude productin HCl/MeOH (2 mL, 0.5 N). The reaction was purged with hydrogen andstirred under H₂ (balloon) at 25° C. for 4 hrs. The reaction mixture wasfiltered through a small Celite plug. The filtrate was concentrated toyield the crude product, which was purified by preparative reverse phaseHPLC on a Waters Autopurification system using a Phenomenex Polymerx 10μRP-γ 100A column [10 μm, 150×21.20 mm; flow rate, 20 mL/min; Solvent A:0.05 N HCl/water; Solvent B: CH₃CN; injection volume: 4.0 mL (0.05 NHCl/water); gradient: 0→70% B over 7 min, 70→100% over 3 min, and 100%over 5 min; mass-directed fraction collection]. Fractions containing thedesired product were collected and freeze-dried to yield 1 mg ofcompound S17-9-1: ¹H NMR (400 MHz, CD₃OD) δ 7.28 (s, 1H), 4.52 (s, 2H),4.12 (s, 1H), 3.52-3.40 (m, 2H), 3.20-2.93 (m, 5H), 3.04 (s, 3H), 2.95(s, 3H), 2.78-2.67 (m, 1H), 2.30-2.23 (m, 1H), 1.80-1.58 (m, 5H), 1.11(s, 3H), 1.04 (s, 3H); MS (ESI) m/z 565.23 (M+H).

The following compound was prepared similarly to S17-9-1.

S17-9-2:

¹H NMR (400 MHz, CD₃OD) δ 7.28 (s, 1H), 4.16 (s, 1H), 4.13 (s, 1H),3.24-2.90 (m, 3H), 3.05 (s, 3H), 2.96 (m, 3H), 2.78 (m, 3H), 2.83-2.66(m, 1H), 2.32-2.24 (m, 1H), 1.74-1.60 (m, 1H), 1.58 (s, 9H); MS (ESI)m/z 539.25 (M+H).

Example 18 Synthesis of Compounds Via Scheme 18

The following compounds were prepared according to Scheme 18.

A solution of benzoic acid S18-1 (17.51 g, 102.90 mmol, 1.0 equiv) inTHF (150 mL) was added dropwise to a solution of s-BuLi (161.70 mL, 1.4M/cyclohexane, 226.40 mmol, 2.2 equiv) and TMEDA (34.00 mL, 226.40 mmol,2.2 equiv) in THF (150 mL) at −78° C. via a cannula over 1 h 30 min. Theresulting orange reaction mixture was stirred at −78° C. for 2 hrs.Iodomethane (8.38 mL, 134.30 mmol, 5.0 equiv) was added at −78° C. whilemanually shaking the reaction mixture. The dry-ice/acetone bath wasremoved, and the resulting white suspension was then stirred at rt for30 min. Water (150 mL) was added. The resulting purple mixture wasconcentrated to remove most of the THF and other organic volatiles.Aqueous NaOH (6 M, 100 mL) was added. The mixture was extracted withmethyl t-butyl ether (2×200 mL). The aqueous layer was acidified withaqueous HCl (170 mL, 6 N) to pH 1, and extracted with EtOAc (150 mL,then 2×80 mL). The combined organic phase was dried over magnesiumsulfate, filtered and concentrated to afford the crude product as anorange solid (15.03 g, containing the desired product S18-2, theregioisomer (i.e. 2-methoxy-3-methyl-4-fluoro benzoic acid) and startingmaterial S18-1 at a ratio of 1.7:3:0.9 as indicated by ¹H NMR analysis).

The above crude product was dissolved in dichloromethane (50 mL). Oxalylchloride (2.66 mL, 30.44 mmol, 1.1 equiv) was added at rt followed by acouple of drops of DMF. The mixture was stirred at rt for 1 h and thesolvent was evaporated. The residue was dried under high vacuum. Theresulting orange oil was re-dissolved in dichloromethane (50 mL). Phenol(2.86 g, 30.44 mmol, 1.1 equiv), triethylamine (7.70 mL, 55.35 mmol, 2.0equiv), and DMAP (catalytic amount) were added. The reaction mixture wasstirred at rt for 1 h. Solvents were evaporated and the residue wasdissolved in EtOAc (150 mL) and water (50 mL). The organic layer waswashed with aqueous HCl (50 mL, 1 N), 1 N aqueous NaOH (2×30 mL) andbrine (50 mL), dried over anhydrous magnesium sulfate, filtered andconcentrated. The residue was purified by flash column chromatography(1-4% EtOAc/hexanes) to afford the desired product S18-3 as a yellowsolid (2.73 g, 41% over five steps): ¹H NMR (400 MHz, CDCl₃) δ 7.45-7.41(m, 2H), 7.29-7.22 (m, 3H), 6.59-6.53 (m, 2H), 3.87 (s, 3H), 2.43 (s,3H); MS (ESI) m/z 259.15 (M+H).

A solution of BBr₃ in dichloromethane (10.49 mL, 1.0 M, 10.49 mmol, 1.0equiv) was added slowly to a solution of the above compound S18-3 (2.73g, 10.49 mmol, 1.0 equiv) in dichloromethane (50 mL) at −78° C. Theresulting orange solution was stirred at −78° C. for 10 min and then at0° C. for 15 min. Saturated aqueous NaHCO₃ (30 mL) was added slowly. Theresulting mixture was stirred at rt for 5 min and the dichloromethanewas evaporated. The residue was extracted with EtOAc (80 mL, then 30mL). The organic extracts were combined, dried over anhydrous magnesiumsulfate, filtered, and concentrated to afford an orange solid, which wasused directly in the next reaction.

Di-t-butyl dicarbonate (2.40 g, 11.01 mmol, 1.05 equiv) andN,N-dimethylaminopyridine (catalytic amount) were added to a solution ofthe above product in dichloromethane (50 mL). The reaction was stirredfor 40 min at rt (monitored by LC-MS and TLC (product is slightly morepolar)), and concentrated. The residue was purified by flash columnchromatography (1-5% EtOAc/hexanes containing 10% dichloromethane) toafford product S18-4 as a white solid (3.45 g, 95% for two steps): ¹HNMR (400 MHz, CDCl₃) δ 7.46-7.42 (m, 2H), 7.31-7.24 (m, 3H), 6.94-6.88(m, 2H), 2.54 (s, 3H), 1.45 (s, 9H); MS (ESI) m/z 345.25 (M+H).

A solution of ester S18-4 (0.50 g, 1.45 mmol, 1.0 equiv) in THF (2.5 mL)was added to a solution of LDA (1.87 mL, 1.55M/THF/heptane/ethylbenzene, 2.90 mmol, 2.0 equiv) and TMEDA (0.44 mL,2.90 mmol, 2.0 equiv) in THF (20 mL) via a cannula. The reaction mixturewas stirred at −78° C. for 15 min. A solution of enone S1-9 (0.49 g,1.01 mmol, 0.7 equiv) in THF (2.5 mL) was added to the reaction mixturevia a cannula. The reaction mixture was then allowed to warm to 0° C.over 1 h, quenched by saturated aqueous NH₄Cl, and extracted with EtOAc(70 mL). The combined organic extracts were dried (sodium sulfate),filtered and concentrated. The residue was purified by flash columnchromatography (5-10% EtOAc/hexanes) to yield the desired product S18-5(0.28 g, 37%): ¹H NMR (400 MHz, CDCl₃) δ 13.97 (br s, 1H), 7.49-7.47 (m,2H), 7.39-7.32 (m, 3H), 6.44 (d, J=9.2 Hz, 1H), 5.35 (s, 2H), 3.86 (d,J=10.4 Hz, 1H), 3.08-3.00 (m, 1H), 2.94-2.90 (m, 1H), 2.81-2.73 (m, 1H),2.46-2.41 (m, 9H), 1.56 (s, 9H), 0.83 (s, 9H), 0.27 (s, 3H), 0.12 (s,3H); MS (ESI) m/z 735.41 (M+H). Some unreacted enone S1-9 (0.17 g) wasalso recovered.

Aqueous HF (48-50%, 0.4 mL) was added to a solution of compound S18-5(0.28 g, 0.37 mmol) in acetonitrile (1.2 mL) in a polypropylene reactionvessel at 23° C. The resulting mixture was stirred vigorously at 23° C.overnight and poured into aqueous K₂HPO₄ (4.8 g dissolved in 30 mLwater). The mixture was extracted with 5% MeOH in EtOAc (4×60 mL). Thecombined organic extracts were dried over anhydrous sodium sulfate,filtered, and concentrated. The residue was purified by preparativereverse phase HPLC on a Waters Autopurification system using a SunfirePrep C18 OBD column [5 μm, 19×50 mm; flow rate, 20 mL/min; Solvent A:H₂O with 0.1% HCO₂H; Solvent B: CH₃CN with 0.1% HCO₂H; injection volume:3.0 mL (CH₃CN); gradient: 0→100% B in A over 10 min; mass-directedfraction collection] to yield S18-6-1 and S18-6-2.

S18-6-1

(54 mg, 23%): ¹H NMR (400 MHz, CD₃OD) δ 14.49 (br s, 1H), 12.45 (br s,1H), 7.46-7.41 (m, 2H), 7.38-7.30 (m, 3H), 6.37 (d, J=9.2 Hz, 1H), 5.34(s, 2 H), 3.78 (br s, 1H), 2.96-2.93 (m, 2H), 2.72-2.67 (m, 1H),2.61-2.46 (m, 7H), 2.05-2.02 (m, 1H), 1.56 (s, 9H); MS (ESI) m/z 621.19(M+H).

S18-6-2

(0.16 g, 77%): ¹H NMR (400 MHz, CD₃OD) δ 7.40-7.38 (m, 2H), 7.32-7.26(m, 3H), 6.53 (d, J=9.6 Hz, 1H), 5.32, 5.28 (Abq, J=11.9 Hz, 2H),3.35-3.31 (m, 1H), 3.25-2.98 (m, 9H), 2.76-2.71 (m, 1H), 2.44 (t, J=14.6Hz, 1H), 2.06-2.02 (m, 1H); MS (ESI) m/z 565.18 (M+H).

Pd—C (10 wt %, 15 mg) was added in one portion into a solution ofcompound S18-6-1 (54 mg, 0.087 mmol) in a mixture of MeOH (3 mL) anddioxane (0.5 mL) at 23° C. The reaction vessel was sealed and purgedwith hydrogen by briefly evacuating the flask followed by flushing withhydrogen gas (1 atm). The resulting mixture was stirred at 23° C. for 50min. The reaction mixture was then filtered through a small Celite pad.The filtrate was concentrated. The residue was purified by preparativereverse phase HPLC on a Waters Autopurification system using aPhenomenex Polymerx 10μ RP-γ 100A column [10 μm, 150×21.20 mm; flowrate, 20 mL/min; Solvent A: 0.05 N HCl/water; Solvent B: CH₃CN;injection volume: 3.0 mL (0.05 N HCl/water); gradient: 20→80% B over 10min; mass-directed fraction collection]. Fractions containing thedesired product, eluting at 6.7-7.6 min, were collected and freeze-driedto yield compound S18-7-1 (29 mg, 59%): ¹H NMR (400 MHz, CD₃OD) δ 6.62(d, J=9.6 Hz, 1H), 4.09 (s, 1H), 3.07-2.94 (m, 8H), 2.90-2.85 (m, 1H),2.57 (t, J=14.6 Hz, 1H), 2.21-2.16 (m, 1H), 1.61-1.57 (m, 1H), 1.57 (s,9H); MS (ESI) m/z 533.25 (M+H).

Compound S18-7-2 was prepared similarly.

S18-7-2:

¹H NMR (400 MHz, CD₃OD) δ 6.65 (d, J=10.1 Hz, 1H), 4.09 (s, 1H),3.10-2.94 (m, 8H), 2.89 (dd, J=4.1, 15.6 Hz, 1H), 2.58 (t, J=14.6 Hz,1H), 2.22-2.17 (m, 1H), 1.63-1.54 (m, 1H); MS (ESI) m/z 477.16 (M+H).

A mixture of compound S18-6-2 (27 mg, 0.048 mmol, 1.0 equiv), EDC (18mg, 0.095 mmol, 2.0 equiv) and HOBt (3 mg, 0.024 mmol, 0.5 equiv) weredissolved in DMF (0.5 mL). Neopentylamine (11 μL, 0.095 mmol, 2.0 equiv)was added. The reaction mixture was stirred at it overnight and filteredthrough a cotton plug. The cotton plug was washed with acetonitrile (1mL). The filtrate was purified by preparative reverse phase HPLC on aWaters Autopurification system using a Sunfire Prep C18 OBD column [5μm, 19×50 mm; flow rate, 20 mL/min; Solvent A: H₂O with 0.1% HCO₂H;Solvent B: CH₃CN with 0.1% HCO₂H; injection volume: 3.0 mL (CH₃CN);gradient: 0→60% B in A over 10 min; mass-directed fraction collection].Fractions containing the desired product, eluting at 7.8-8.7 min, werecollected and freeze-dried to yield compound S18-8-1 (14 mg, 46%): ¹HNMR (400 MHz, CDCl₃) δ 7.50-7.47 (m, 2H), 7.42-7.36 (m, 3H), 6.62 (d,J=9.6 Hz, 1H), 5.42, 5.38 (Abq, J=11.9 Hz, 2H), 4.82 (d, J=1.4 Hz, 1H),3.41-3.38 (m, 1H), 3.20-3.16 (m, 2H), 3.16 (s, 3H), 3.09-3.01 (m, 1H),2.83 (dd, J=4.1, 15.6 Hz, 1H), 2.54 (t, J=14.6 Hz, 1H), 2.13-2.08 (m,1H), 1.42-1.32 (m, 1H), 0.98 (s, 9H); MS (ESI) m/z 634.26 (M+H).

Pd—C (10 wt %, 5 mg) was added in one portion into a solution ofcompound S18-8-1 (14 mg, 0.022 mmol) in MeOH (3 mL) at 23° C. Thereaction vessel was sealed and purged with hydrogen by brieflyevacuating the flask followed by flushing with hydrogen gas (1 atm). Thereaction mixture was stirred at 23° C. for 30 min. The reaction mixturewas then filtered through a small Celite pad. The filtrate wasconcentrated. The residue was purified by preparative reverse phase HPLCon a Waters Autopurification system using a Phenomenex Polymerx 10μ RP-γ100A column [10 μm, 150×21.20 mm; flow rate, 20 mL/min; Solvent A: 0.05N HCl/water; Solvent B: CH₃CN; injection volume: 3.0 mL (0.05 NHCl/water); gradient: 15→70% B over 10 min; mass-directed fractioncollection]. Fractions containing the desired product, eluting at7.1-8.8 min, were collected and freeze-dried to yield compound S18-9-1(8 mg, 64%): ¹H NMR (400 MHz, CD₃OD) δ 6.64 (d, J=9.2 Hz, 1H), 4.08 (s,1H), 3.18 (s, 2H), 3.10-2.95 (m, 8H), 2.91-2.86 (m, 1H), 2.57 (t, J=14.6Hz, 1H), 2.20-2.17 (m, 1H), 1.63-1.54 (m, 1H), 0.98 (s, 9H); MS (ESI)m/z 546.23 (M+H).

The following compounds were prepared similarly to S18-8-1 or S18-9-1.

S18-8-2:

¹H NMR (400 MHz, CDCl₃) δ 7.49-7.47 (m, 2H), 7.42-7.36 (m, 3H), 6.66 (d,J=9.6 Hz, 1H), 5.42, 5.38 (Abq, J=11.9 Hz, 2H), 4.81 (d, J=1.4 Hz, 1H),3.60 (t, J=6.9 Hz, 2H), 3.41-3.32 (m, 3H), 3.16 (s, 6H), 3.11-3.02 (m,1H), 2.83 (dd, J=4.1, 15.6 Hz, 1H), 2.56 (t, J=15.1 Hz, 1H), 2.11-2.07(m, 1H), 2.03-1.90 (m, 4H), 1.43-1.33 (m, 1H); MS (ESI) m/z 618.26(M+H).

S18-9-2:

¹H NMR (400 MHz, CD₃OD) δ6.69 (d, J=9.2 Hz, 1H), 4.10 (s, 1H), 3.60 (t,J=6.6 Hz, 2H), 3.47-3.30 (m, 2H), 3.12-2.89 (m, 9H), 2.58 (t, J=14.6 Hz,1H), 2.22-2.18 (m, 1H), 2.02-1.93 (m, 4H), 1.63-1.54 (m, 1H); MS (ESI)m/z 530.20 (M+H).

S18-8-3:

¹H NMR (400 MHz, CDCl₃) δ 7.46-7.44 (m, 2H), 7.38-7.32 (m, 3H), 6.43 (d,J=9.8 Hz, 1H), 5.33 (s, 2H), 4.20 (br s, 1H), 3.81-3.80 (m, 2H),3.30-3.29 (m, 2H), 3.09-3.06 (m, 2H), 2.85-2.82 (m, 16H), 2.71-2.68 (m,1H), 2.48-2.44 (m, 1H), 2.14-2.10 (m, 1H), 1.34-1.28 (m, 1H); MS (ESI)m/z 635.27 (M+H).

S18-9-3:

¹H NMR (400 MHz, CD₃OD) δ 6.68 (d, J=9.6 Hz, 1H), 4.10 (s, 1H), 3.77 (t,J=6.0 Hz, 2H), 3.40 (t, J=6.0 Hz, 2H), 3.10-2.88 (m, 19H), 2.58 (t,J=14.2 Hz, 1H), 2.21-2.18 (m, 1H), 1.63-1.54 (m, 1H); MS (ESI) m/z547.23 (M+H).

S18-8-4:

¹H NMR (400 MHz, CDCl₃) δ 7.49-7.47 (m, 2H), 7.41-7.35 (m, 3H), 6.61 (d,J=9.6 Hz, 1H), 5.41, 5.37 (Abq, J=11.9 Hz, 2H), 4.80 (d, J=0.92 Hz, 1H),3.55-3.52 (m, 4H), 3.40-3.36 (m, 1H), 3.36 (s, 3H), 3.15 (s, 6H),3.08-2.99 (m, 1H), 2.81 (dd, J=4.6, 15.6 Hz, 1H), 2.53 (t, J=14.6 Hz,1H), 2.12-2.09 (m, 1H), 1.41-1.32 (m, 1H); MS (ESI) m/z 622.27 (M+H).

S18-9-4:

¹H NMR (400 MHz, CD₃OD) δ 6.63 (d, J=9.6 Hz, 1H), 4.07 (s, 1H),3.56-3.52 (m, 4H), 3.37 (s, 3H), 3.10-2.93 (m, 8H), 2.90-2.86 (m, 1H),2.57 (t, J=14.2 Hz, 1H), 2.19-2.16 (m, 1H), 1.63-1.54 (m, 1H); MS (ESI)m/z 534.19 (M+H).

Example 19 Synthesis of Compounds Via Scheme 19

The following compounds were prepared according to Scheme 19.

NBS (0.79 g, 4.44 mmol, 1.2 equiv) and AIBN (61 mg, 0.37 mmol, 0.10equiv) were added to a suspension of compound S18-4 (1.28 g, 3.70 mmol,1.0 equiv) in carbon tetrachloride (37 mL) at rt. The resulting mixturewas stirred at 80° C. for 16 hrs, cooled to rt, and diluted withdichloromethane (40 mL). The resulting mixture was washed with saturatedaqueous NaHCO₃ and brine (1:1, 40 mL). The aqueous layer was furtherextracted with dichloromethane (2×15 mL). The combined organic phase wasdried over anhydrous magnesium sulfate, filtered, and concentrated. Theresidue was purified by flash column chromatography (0-5% EtOAc/hexanes)to afford the desired product S19-1 as a white solid (1.04 g, 66%): ¹HNMR (400 MHz, CDCl₃) δ 7.45-7.41 (m, 2H), 7.30-7.27 (m, 3H), 7.10 (dd,J=2.8, 8.7 Hz, 1H), 7.01 (dd, J=2.8, 8.7 Hz, 1H), 4.70 (s, 2H), 1.44 (s,9H); MS (ESI) m/z 423.16, 425.13 (M−H).

A solution of phenyllithium in di-n-butyl ether (1.22 mL, 1.8 M, 2.20mmol, 3.0 equiv) was added dropwise via a syringe to a solution of S19-1(0.94 g, 2.20 mmol, 3.0 equiv) and enone S1-9 (0.35 g, 0.73 mmol, 1.0equiv) in THF (37 mL) at −100° C. The orange reaction mixture wasallowed to warm to −78° C. over 10 min. Then a solution of LHMDS inhexanes (0.73 mL, 1.0 M/THF, 0.73 mmol, 1.0 equiv) was added dropwise at−78° C. The reaction mixture was allowed to warm slowly to −10° C. over50 min, and then partitioned between aqueous potassium phosphate buffersolution (pH 7, 0.2 M, 50 mL) and EtOAc (120 mL). The phases wereseparated and the organic phase was dried over anhydrous sodium sulfate,filtered, and concentrated. The residue was purified by preparativereverse phase HPLC on a Waters Autopurification system using a SunfirePrep C18 OBD column [5 μm, 19×50 mm; flow rate, 20 mL/min; Solvent A:H₂O with 0.1% HCO₂H; Solvent B: CH₃CN with 0.1% HCO₂H; injection volume:3.0 mL (CH₃CN); gradient: 80→100% B in A over 10 min; mass-directedfraction collection]. Fractions containing the desired product, elutingat 4.3-6.8 min, were collected and concentrated to yield compound S19-2(0.49 g, 90%): ¹H NMR (400 MHz, CDCl₃) δ 15.69 (s, 1H), 7.49-7.47 (m,2H), 7.38-7.32 (m, 3H), 6.84 (d, J=7.9 Hz, 1H), 6.80 (d, J=8.5 Hz, 1H),5.34 (s, 2H), 3.92 (d, J=10.4 Hz, 1H), 3.10-3.03 (m, 1H), 2.94-2.78 (m,2H), 2.52-2.40 (m, 8H), 2.07 (d, J=14.6 Hz, 1H), 1.98 (s, 9H), 1.53 (s,9H), 0.26 (s, 3H), 0.11 (s, 3H); MS (ESI) m/z 735.35 (M+H).

Aqueous HF (48-50%, 0.5 mL) was added to a solution of compound S19-2(0.49 g, 0.66 mmol) in acetonitrile (1.0 mL) in a polypropylene reactionvessel at 23° C. The mixture was stirred vigorously at 23° C. overnight,poured into aqueous K₂HPO₄ (6 g dissolved in 40 mL water), and extractedwith EtOAc (100 mL, then 2×20 mL). The combined organic extracts weredried over anhydrous sodium sulfate, filtered, and concentrated. Theresidue was used directly in the next step.

Pd—C (10 wt %, 10 mg) was added in one portion into a solution of theabove product in a mixture of MeOH (2 mL) and dioxane (0.5 mL) at 23° C.The reaction vessel was sealed and purged with hydrogen by brieflyevacuating the flask followed by flushing with hydrogen gas (1 atm). Thereaction was stirred at 23° C. for 30 min. The reaction mixture was thenfiltered through a small Celite pad. The filtrate was concentrated. Theresidue was purified by preparative reverse phase HPLC on a WatersAutopurification system using a Phenomenex Polymerx 10 Pt RP-γ 100Acolumn [10 μm, 150×21.20 mm; flow rate, 20 mL/min; Solvent A: 0.05 NHCl/water; Solvent B: CH₃CN; injection volume: 3.0 mL (0.05 NHCl/water); gradient: 15-60% B over 10 min; mass-directed fractioncollection]. Fractions containing the desired product were collected andfreeze-dried to yield compound S19-3 (0.22 g, 66% over 2 steps): ¹H NMR(400 MHz, CD₃OD) δ 6.65-6.52 (m, 2H), 4.08 (s, 1H), 3.06-2.93 (m, 8H),2.86 (dd, J=4.1, 15.1 Hz, 1H), 2.54 (t, J=14.6 Hz, 1H), 2.21-2.16 (m,1H), 1.62-1.53 (m, 1H); MS (ESI) m/z 433.19 (M+H).

Compound S19-3 (0.15 g, 0.31 mmol, 1.0 equiv) was dissolved inconcentrated sulfuric acid (1 mL) at 0° C., forming a red solution.NaNO₃ (39 mg, 0.46 mmol, 1.5 equiv) was then added in one portion at 0°C. The resulting orange reaction mixture was stirred at 0° C. for 30min, and was then added dropwise to vigorously stirring diethyl ether(100 mL). The precipitates were collected onto a small Celite pad,washed with more ether, and eluted with MeOH (20 mL). The MeOH solutionwas concentrated. The residue was used directly in the next step.

Pd—C (10 wt %, 50 mg) was added in one portion into a solution of theabove products in MeOH (5 mL) at 23° C. The reaction vessel was sealedand purged with hydrogen by briefly evacuating the flask followed byflushing with hydrogen gas (1 atm). The mixture was stirred at 23° C.for 1 h. The reaction mixture was then filtered through a small Celitepad. The filtrate was concentrated. The residue was purified bypreparative reverse phase HPLC on a Waters Autopurification system usinga Phenomenex Polymerx 10μ RP-γ 100A column [10 μm, 150×21.20 mm; flowrate, 20 mL/min; Solvent A: 0.05 N HCl/water; Solvent B: CH₃CN;injection volume: 3.0 mL (0.05 N HCl/water); gradient: 5-30% B over 24min; mass-directed fraction collection] to yield compound S19-4 andS19-5.

Compound S19-4 (18 mg): ¹H NMR (400 MHz, CD₃OD) δ 6.88 (d, J=11.9 Hz,1H), 4.15 (s, 1H), 3.20-2.95 (m, 9H), 2.45 (t, J=15.6 Hz, 1H), 2.34-2.29(m, 1H), 1.69-1.59 (m, 1H); MS (ESI) m/z 448.18 (M+H).

Compound S19-5 (68 mg, 72% over 2 steps): ¹H NMR (400 MHz, CD₃OD) δ 6.87(d, J=9.2 Hz, 1H), 4.16 (s, 1H), 3.16-2.94 (m, 9H), 2.60 (t, J=14.6 Hz,1H), 2.28-2.24 (m, 1H), 1.64-1.55 (m, 1H); MS (ESI) m/z 448.18 (M+H).

2-t-Butylaminoacetyl chloride hydrochloride (4 mg, 0.020 mmol, 2.0equiv) was added to a solution of compound S19-4 (5 mg, 0.010 mmol, 1.0equiv) in DMF (0.3 mL) at rt. The resulting orange reaction mixture wasstirred at rt for 15 min and quenched by aqueous HCl (0.5 N, 2 mL). Theresulting mixture was purified by preparative reverse phase HPLC on aWaters Autopurification system using a Phenomenex Polymerx 10μ RP-γ 100Acolumn [10 μm, 150×21.20 mm; flow rate, 20 mL/min; Solvent A: 0.05 NHCl/water; Solvent B: CH₃CN; injection volume: 3.0 mL (0.05 NHCl/water); gradient: 0→30% B over 20 min; mass-directed fractioncollection]. Fractions containing the desired product, eluting at12.4-13.6 min, were collected and freeze-dried to yield compound S19-7-1(4 mg, 56%): ¹H NMR (400 MHz, CD₃OD) δ 6.71 (d, J=11.4 Hz, 1H), 4.11 (s,1H), 4.06 (s, 2H), 3.12-3.08 (m, 1H), 3.07-2.96 (m, 8H), 2.31-2.24 (m,2H), 1.62-1.52 (m, 1H), 1.41 (s, 9H); MS (ESI) m/z 561.39 (M+H).

Compound S19-6-1 was prepared from S19-5 with the same procedure: ¹H NMR(400 MHz, CD₃OD) δ 6.70 (d, J=9.6 Hz, 1H), 4.10 (s, 1H), 4.05 (s, 2H),3.09-2.93 (m, 8H), 2.92-2.87 (m, 1H), 2.57 (t, J=14.2 Hz, 1H), 2.29-2.19(m, 1H), 1.64-1.54 (m, 1H), 1.41 (s, 9H); MS (ESI) m/z 561.30 (M+H).

Pd—C (10 wt %, 6 mg) and formaldehyde in water (37%, 9 μL, 0.12 mmol,5.0 equiv) were added to a solution of compound S19-4 (12 mg, 0.024mmol, 1.0 equiv) in MeOH (1 mL) at 23° C. The reaction vessel was sealedand purged with hydrogen by briefly evacuating the flask followed byflushing with hydrogen gas (1 atm). The resulting mixture was stirred at23° C. for 4 hrs. The reaction mixture was then filtered through a smallCelite pad. The filtrate was concentrated. The residue was purified bypreparative reverse phase HPLC on a Waters Autopurification system usinga Phenomenex Polymerx 10μ RP-γ 100A column [10 μm, 150×21.20 mm; flowrate, 20 mL/min; Solvent A: 0.05 N HCl/water; Solvent B: CH₃CN;injection volume: 3.0 mL (0.05 N HCl/water); gradient: 15-60% B over 10min; mass-directed fraction collection]. Fractions containing thedesired product, eluting at 4.9-6.1 min, were collected and freeze-driedto yield compound S19-7-2 (9 mg, 68%): ¹H NMR (400 MHz, CD₃OD) δ 6.86(d, J=14.2 Hz, 1H), 4.16 (s, 1H), 3.49 (dd, J=4.1, 15.6 Hz, 1H), 3.24(br s, 6H), 3.12-3.02 (m, 2H), 3.06 (s, 3H), 2.97 (s, 3H), 2.48 (t,J=14.6 Hz, 1H), 2.33-2.30 (m, 1H), 1.70-1.61 (m, 1H); MS (ESI) m/z476.24 (M+H).

Benzyl N-(hydroxymethyl)carbamate (10 mg, 0.057 mmol, 1.1 equiv) wasadded to a solution of compound S19-3 (24 mg, 0.052 mmol, 1.0 equiv) ina mixture of TFA (0.2 mL) and methanesulfonic acid (0.1 mL) at rt. Thereaction mixture was stirred at rt for 14 hrs. More benzylN-(hydroxymethyl)carbamate (5 mg, 0.026 mmol, 0.5 equiv) was added. Thereaction mixture was stirred at rt for another hour, quenched by 0.05 NHCl/water (1 mL), filtered through a cotton plug, and the cotton plugwas washed with 0.05 N HCl/water. The filtrate was purified bypreparative reverse phase HPLC on a Waters Autopurification system usinga Phenomenex Polymerx 10μ RP-γ 100A column [10 μm, 150×21.20 mm, flowrate, 20 mL/min; Solvent A: 0.05 N HCl/water; Solvent B: CH₃CN;injection volume: 3.0 mL (0.05 N HCl/water); gradient: 0→20% B over 22min; mass-directed fraction collection]. Fractions containing thedesired product, eluting at 12.2-15.2 min, were collected andfreeze-dried to yield the aminomethylated intermediates as a mixture ofregioisomers (˜3:2, 10 mg, 36%): ¹H NMR (400 MHz, CD₃OD) δ 6.73-6.71 (m,1H), 4.19 (s, 1H), 4.15 (s, 0.4H), 4.11 (s, 0.6H), 3.27-3.22 (m, 0.4H),3.14-2.90 (m, 9.6H), 2.58 (t, J=14.6 Hz, 0.6H), 2.45 (t, J=14.2 Hz,0.4H), 2.34-2.31 (m, 0.4H), 2.24-2.20 (m, 0.6H), 1.64-1.54 (m, 1H); MS(ESI) m/z 462.22 (M+H).

A solution of pivalaldehyde (2 μL, 0.021 mmol, 1.1 equiv) in DMF (0.2mL) was added to the above aminomethylated intermediates. Triethylamine(5 μL, 0.038 mmol, 2.0 equiv) was added. The reaction mixture wasstirred at rt for 50 min. Na(OAc)₃BH (8 mg, 0.038 mmol, 2.0 equiv) wasadded. After 35 min, more pivalaldehyde (0.5 μL, 0.0050 mmol, 0.25equiv) was added. The reaction mixture was stirred at rt for another 40min, diluted with 0.05 N HCl/water, and purified by preparative reversephase HPLC on a Waters Autopurification system using a PhenomenexPolymerx 10μ RP-γ 100A column [10 μm, 150×21.20 mm; flow rate, 20mL/min; Solvent A: 0.05 N HCl/water; Solvent B: CH₃CN; injection volume:3.0 mL (0.05 N HCl/water); gradient: 0→20% B over 20 min, and then keptat 20% B for 5 min; mass-directed fraction collection]. Fractionscontaining the desired product, eluting at 21.0-21.5 min, were collectedand freeze-dried to yield product S19-8-1 (1 mg, 10%): ¹H NMR (400 MHz,CD₃OD) δ 6.77 (d, J=10.1 Hz, 1H), 4.34 (s, 2H), 4.09 (s, 1H), 3.04 (s,2H), 2.98-2.92 (m, 9H), 2.62 (t, J=14.6 Hz, 1H), 2.23-2.17 (m, 1H),1.66-1.56 (m, 1H), 1.09 (s, 9H); MS (ESI) m/z 532.36 (M+H).

Example 20 Synthesis of Compounds Via Scheme 20

The following compounds were prepared according to Scheme 20.

Crude S18-2 (9.4 g, ˜51 mmol, 1.0 equiv) was dissolved in TFA (50 mL)and cooled to 0° C. NBS (9.54 g, 53.60 mmol, 1.05 equiv) was added inone portion. The reaction mixture was stirred at 0° C. for 1 h.Volatiles were evaporated, and the mixture was poured onto ice-water(300 mL). The resulting mixture was extracted with EtOAc (300 mL). Thecombined organic phases were washed with brine (100 mL), dried overanhydrous magnesium sulfate, filtered, concentrated, and further driedunder high vacuum to give crude S20-1, which was used in the nextreaction without further purification.

The above crude product S20-1 was dissolved in dichloromethane (100 mL).Oxalyl chloride (5.78 mL, 66.30 mmol, 1.3 equiv) was added at rt(bubbling vigorously). Additional amounts of oxalyl chloride [3×(5.78mL, 66.30 mmol, 1.3 equiv)] were added, followed by a few drops of DMF.The mixture was stirred at rt for 1 h. Volatiles were evaporated, andthe residue was further dried under high vacuum to afford the crude acidchloride. The crude acid chloride was redissolved in dichloromethane(100 mL). Phenol (5.76 g, 61.20 mmol, 1.2 equiv), triethylamine (21.30mL, 153.00 mmol, 3.0 equiv), and DMAP (catalytic amount) were added. Thereaction mixture was stirred overnight at rt. Volatiles were evaporated.The residue was dissolved in EtOAc (300 mL) and water (100 mL). Theorganic layer was separated and washed with 1 N aqueous HCl (70 mL),brine (50 mL), 1 N aqueous NaOH (70 mL) and brine (50 mL), dried overanhydrous magnesium sulfate, filtered, and concentrated. The residue waspurified by hydrolysis of the byproducts as following.

The above crude product was dissolved in 2-methyltetrahydrofuran (25mL). Water (25 mL) was added, followed by 50 wt % aqueous NaOH (˜19N,2.70 mL). The reaction mixture was stirred vigorously at 75° C. for 3hrs (monitored by LC-MS). The reaction mixture was cooled to rt dilutedwith EtOAc (200 mL). The organic phase was washed with 2 N aqueous NaOH(2×45 mL) and brine (50 mL), dried over anhydrous magnesium sulfate,filtered, and concentrated to afford the desired product S20-2 (10.00g): ¹H NMR (400 MHz, CDCl₃) δ 7.46-7.42 (m, 2H), 7.31-7.29 (m, 1H),7.26-7.22 (m, 2H), 6.67 (d, J=10.4 Hz, 1H), 3.88 (s, 3H), 2.52 (s, 3H);MS (ESI) m/z 337.15, 339.12 (M−H).

A solution of BBr₃ in dichloromethane (29.48 mL, 1.0 M, 29.48 mmol, 1.0equiv) was added slowly to a solution of the above compound S20-2 indichloromethane (100 mL) at −78° C. The resulting red solution wasallowed to warm to 0° C. in 25 min and kept at that temperature for 10min (monitored by LC-MS or TLC (product is slightly less polar)). Thereaction mixture was poured into saturated NaHCO₃ solution (100 mL),stirred at rt for 5 min, and concentrated under reduced pressure. Theresidue was extracted with EtOAc (180 mL, then 30 mL). The organicextracts were combined and dried over anhydrous magnesium sulfate,filtered, and concentrated to afford the crude phenol, which was useddirectly in the next reaction:

¹H NMR (400 MHz, CDCl₃) δ 11.01 (d, J=1.2 Hz, 1H), 7.48-7.44 (m, 2H),7.34-7.30 (m, 1H), 7.19-7.17 (m, 2H), 6.72 (d, J=9.2 Hz, 1H), 2.85 (s,3H); MS (ESI) m/z 323, 325 (M−H).

Benzylbromide (3.67 mL, 30.95 mmol, 1.05 equiv) and Cs₂CO₃ powder (11.50g, 35.38 mmol, 1.2 equiv) were added to a solution of the above crudephenol (10.00 g, 29.48 mmol, 1.0 equiv) in acetone (60 mL). The mixturewas stirred at rt overnight. Solvents were evaporated and the residuewas dissolved in a mixture of EtOAc (250 mL), water and brine (1:1, 150mL). The organic layer was separated, and the aqueous layer wasextracted with EtOAc (50 mL). The combined organic phase was dried overanhydrous magnesium sulfate, filtered, and concentrated. The residue waspurified by flash column chromatography (1% EtOAc/hexanes), followed byre-crystallization from EtOAc/hexanes to afford the desired productS20-3 as a white solid (6.30 g, 24% five steps): ¹H NMR (400 MHz, CDCl₃)δ 7.42-7.33 (m, 7H), 7.26-7.22 (m, 1H), 7.08-7.05 (m, 2H), 6.70 (d,J=9.8 Hz, 1H), 5.12 (s, 2H), 2.51 (s, 3H); MS (ESI) m/z 413.27, 415.22(M−H).

To a solution of S20-3 (1.33 g, 3.19 mmol, 1.0 equiv) and TMEDA (0.96mL, 6.39 mmol, 2.0 equiv) in THF (50 mL) was added dropwise a solutionof LDA (5.32 mL, 1.2 M/THF/heptane/ethylbenzene, 6.39 mmol, 2.0 equiv)at −78° C. The resulting red solution was stirred at that temperaturefor 15 min, and DMF (0.74 mL, 9.58 mmol, 3.0 equiv) was added. Thereaction mixture was stirred at −78° C. for 1 h (monitored by LC-MS andTLC). Saturated aqueous NH₄Cl (10 mL) was added at −78° C. dropwise. Theresulting mixture was warmed up to rt, diluted with water (50 mL) andextracted with EtOAc (200 mL). The organic phase was dried overanhydrous magnesium sulfate, filtered, and concentrated. The residue waspurified by flash column chromatography (3-6% EtOAc/hexanes) to affordthe desired compound S20-4 as an off-white solid (0.53 g): ¹H NMR (400MHz, CDCl₃) δ 10.27 (s, 1H), 7.45-7.42 (m, 2H), 7.38-7.34 (m, 5H),7.27-7.24 (m, 1H), 7.03-7.01 (m, 2H), 5.12 (s, 2H), 2.60 (s, 3H); MS(ESI) m/z 441.20, 443.25 (M−H).

To a solution of S20-4 (0.53 g, 1.20 mmol, 1.0 equiv) in EtOH (3 mL) anddichloromethane (2 mL) was added NaBH₄ (45 mg, 1.20 mmol, 1.0 equiv) atrt in one portion (exothermic). After 1 min, TLC showed the reaction wascomplete. The reaction mixture was then cooled to 0° C., and 1 N aqueousHCl solution (1 mL) was added dropwise (gas evolution). Aqueoussaturated NaHCO₃ was added to neutralize the aqueous layer to pH 7. Theresulting mixture was extracted with dichloromethane (50 mL). Theorganic phase was dried over anhydrous magnesium sulfate, filtered, andconcentrated. The residue was purified by flash column chromatography(10% EtOAc/hexanes) to afford the desired compound S20-5 as a whitesolid (0.62 g, 43% over two steps): ¹H NMR (400 MHz, CDCl₃) δ 7.43-7.35(m, 7H), 7.28-7.24 (m, 1H), 7.09-7.08 (m, 2H), 5.14 (s, 2H), 4.73 (dd,J=1.8, 6.7 Hz, 2H), 2.55 (s, 3H), 1.92 (t, J=6.7 Hz, 1H); MS (ESI) m/z443.10, 445.09 (M−H).

A solution of n-butyllithium in hexanes (1.36 mL, 1.6 M, 2.18 mmol, 2.2equiv) was added to a solution of diisopropylamine (0.31 mL, 2.18 mmol,2.2 equiv) and TMEDA (0.33 mL, 2.18 mmol, 2.2 equiv) in THF (20 mL) at−78° C. After stirring at −78° C. for 30 min, a solution of compoundS20-5 (0.44 g, 0.99 mmol, 1.0 equiv) in THF (4 mL) was added dropwisevia a cannula. The resulting red reaction mixture was then stirred at−78° C. for 10 min, and cooled to −100° C. A solution of enone S1-9(0.38 g, 0.79 mmol, 0.8 equiv) in THF (4 mL) was added to the reactionmixture via a cannula. The resulting reaction mixture was allowed towarm to −30° C. over 1.5 hrs, quenched by saturated aqueous NH₄Cl (40mL), and extracted with EtOAc (100 mL). The organic phase were dried(sodium sulfate), filtered and concentrated. The residue was purified bya preparative reverse phase HPLC on a Waters Autopurification systemusing a Sunfire Prep C18 OBD column [5 μm, 19×50 mm; flow rate, 20mL/min; Solvent A: H₂O with 0.1% HCO₂H; Solvent B: CH₃CN with 0.1%HCO₂H; injection volume: 3.0 mL (CH₃CN); gradient: 80→100% B in A over10 min; mass-directed fraction collection]. Fractions containing thedesired product were collected and concentrated to yield compound S20-6(0.36 g, 54%): ¹H NMR (400 MHz, CDCl₃) δ 15.79 (br s, 1H), 7.51-7.48 (m,2H), 7.40-7.33 (m, 8H), 5.36 (s, 2H), 5.13 (d, J=11.0 Hz, 1H), 4.18 (d,J=10.4 Hz, 1H), 4.64 (dd, J=1.2, 12.2 Hz, 1H), 4.53 (dd, J=1.2, 12.2 Hz,1H), 3.93 (d, J=10.4 Hz, 1H), 3.40 (dd, J=10.7, 16.5 Hz, 1H), 3.06-2.99(m, 1H), 2.61-2.57 (m, 1H), 2.54-2.47 (m, 2H), 2.50 (s, 6H), 2.19 (d,J=14.6 Hz, 1H), 1.86 (br s, 1H), 0.83 (s, 9H), 0.29 (s, 3H), 0.14 (s,3H); MS (ESI) m/z 833.41, 835.38 (M+H).

Trifluoroacetic anhydride (0.17 mL, 1.34 mmol, 2.5 equiv) was addeddropwise to a solution of compound S20-6 (0.45 g, 0.54 mmol, 1.0 equiv)and DMSO (0.19 mL, 2.68 mmol, 5.0 equiv) in THF (25 mL) at −20° C. Theresulting orange reaction mixture was stirred at −20° C. for 25 min.triethylamine (0.37 mL, 2.68 mmol, 5.0 equiv) was added. After stirringfor 25 min, saturated aqueous NaHCO₃ (20 mL) was added at −20° C. Theresulting mixture was extracted with EtOAc (80 mL). The organic phasewere dried (sodium sulfate), filtered and concentrated. The residue waspurified by a preparative reverse phase HPLC on a WatersAutopurification system using a Sunfire Prep C18 OBD column [5 μm, 19×50mm; flow rate, 20 mL/min; Solvent A: H₂O with 0.1% HCO₂H; Solvent B:CH₃CN with 0.1% HCO₂H; injection volume: 3.0 mL (CH₃CN); gradient:80-100% B in A over 10 min; mass-directed fraction collection].Fractions containing the desired product were collected and concentratedto yield compound S20-7 (0.30 g, 67%): ¹H NMR (400 MHz, CDCl₃) δ 15.69(s, 1H), 10.12 (d, J=1.2 Hz, 1H), 7.51-7.49 (m, 2H), 7.40-7.32 (m, 8H),5.37 (s, 2H), 5.14 (d, J=11.0 Hz, 1H), 4.93 (d, J=10.4 Hz, 1H), 3.91 (d,J=11.0 Hz, 1H), 3.48-3.44 (m, 1H), 3.07-3.02 (m, 1H), 3.61-3.46 (m, 3H),2.51 (s, 6H), 2.20 (d, J=14.7 Hz, 1H), 1.86 (br s, 1H), 0.83 (s, 9H),0.29 (s, 3H), 0.15 (s, 3H); MS (ESI) m/z 831.53, 833.54 (M+H).

Neopentylamine (46 μL, 0.42 mmol, 2.0 equiv), acetic acid (36 μL, 0.63mmol, 3.0 equiv) and sodium triacetoxyborohydride (67 mg, 0.32 mmol, 1.5equiv) were added sequentially to a solution of compound S20-7 (0.18 g,0.21 mmol, 1.0 equiv) in 1,2-dichloroethane (5 mL) at 23° C. Afterstirring for 1 h, the reaction mixture was quenched by the addition ofsaturated aqueous sodium bicarbonate and pH 7 phosphate buffer (1:1, 30mL) and extracted with dichloromethane (50 mL, then 10 mL). The combinedorganic extracts were dried over anhydrous sodium sulfate, filtered, andconcentrated. The residue was used directly in the next reaction: ¹H NMR(400 MHz, CDCl₃) δ 7.50-7.48 (m, 2H), 7.39-7.31 (m, 8H), 5.36 (s, 2H),5.08 (d, J=10.4 Hz, 1H), 4.84 (d, J=10.4 Hz, 1H), 3.94 (d, J=11.0 Hz,1H), 3.83, 3.77 (ABq, J=12.2 Hz, 2H), 3.43-3.38 (m, 1H), 3.04-2.99 (m,1H), 2.60-2.44 (m, 3H), 2.50 (s, 6H), 2.29-2.16 (m, 3H), 0.82 (s, 9H),0.28 (s, 3H), 0.14 (s, 3H); MS (ESI) m/z 902.51, 904.51 (M+H).

Aqueous HF (48-50%, 0.6 mL) was added to a solution of the above crudeproduct S20-8-1 in acetonitrile (1.2 mL) in a polypropylene reactionvessel at 23° C. The resulting mixture was stirred vigorously at 23° C.overnight and poured into aqueous K₂HPO₄ (7.2 g dissolved in 30 mLwater). The resulting mixture was extracted with EtOAc (50 mL, then 20mL). The combined organic extracts were dried over anhydrous sodiumsulfate, filtered, and concentrated. The residue was dissolved in MeOHcontaining HCl/MeOH (0.5 N, 84 μL, 0.42 mmol, 2.0 equiv), concentrated,and dried under high vacuum. The residue was used directly in the nextstep without further purification.

The above crude product was dissolved in MeOH (5 mL). Pd—C (10 wt %, 58mg) was added in one portion at 23° C. The reaction vessel was sealedand purged with hydrogen by briefly evacuating the flask followed byflushing with hydrogen gas (1 atm). After stirring at 23° C. for 4.5hrs, more Pd—C (10 wt %, 10 mg) was added. The resulting mixture wasstirred for 1 h 20 min and filtered through a small Celite pad. Thefiltrate was concentrated. The residue was purified by a preparativereverse phase HPLC on a Waters Autopurification system using aPhenomenex Polymerx 10μ RP-γ 100A column [10 μm, 150×21.20 mm; flowrate, 20 mL/min; Solvent A: 0.05 N HCl/water; Solvent B: CH₃CN;injection volume: 3.0 mL (0.05 N HCl/water); gradient: 20→80% B over 10min; mass-directed fraction collection]. Fractions containing thedesired product, eluting at 6.4-7.2 min, were collected and freeze-driedto yield compound S19-8-1 (59 mg, 46% for 3 steps).

The following compounds were prepared similarly to S19-8-1 and S20-8-1.

S20-8-2:

¹H NMR (400 MHz, CDCl₃) δ 7.50-7.48 (m, 2H), 7.39-7.32 (m, 8H), 5.36 (s,2H), 5.11 (d, J=10.4 Hz, 1H), 4.77 (d, J=11.0 Hz, 1H), 3.93 (d, J=11.0Hz, 1H), 3.79, 3.68 (ABq, J=12.8 Hz, 2H), 3.39 (dd, J=10.7, 16.5 Hz,1H), 3.04-2.98 (m, 1H), 2.70-2.67 (m, 1H), 2.60-2.56 (m, 1H), 2.53-2.44(m, 2H), 2.50 (s, 6H), 2.18 (d, J=14.0 Hz, 1H), 0.99 (d, J=6.1 Hz, 6H),0.82 (s, 9H), 0.28 (s, 3H), 0.13 (s, 3H); MS (ESI) m/z 874.36, 876.39(M+H).

S20-8-3:

¹H NMR (400 MHz, CDCl₃) δ 7.50-7.48 (m, 2H), 7.39-7.32 (m, 8H), 5.36 (s,2H), 5.12 (d, J=11.0 Hz, 1H), 4.77 (d, J=10.4 Hz, 1H), 3.94 (d, J=10.4Hz, 1H), 3.70, 3.60 (ABq, J=11.6 Hz, 2H), 3.38 (dd, J=4.3, 15.9 Hz, 1H),3.01-2.94 (m, 1H), 2.59-2.45 (m, 3H), 2.50 (s, 6H), 2.17 (d, J=14.6 Hz,1H), 0.03 (s, 9H), 0.82 (s, 9H), 0.28 (s, 3H), 0.12 (s, 3H); MS (ESI)m/z 888.40, 890.40 (M+H).

S20-10-4:

¹H NMR (400 MHz, CD₃OD) δ 66.80 (d, J=10.1 Hz, 1H), 4.54 (dd, J=3.7,13.3 Hz, 1H), 4.41 (d, J=13.3 Hz, 1H), 4.10 (s, 1H), 3.37-3.32 (m, 1H),3.19-2.91 (m, 13H), 2.62 (t, J=14.6 Hz, 1H), 2.24-2.19 (m, 1H),1.65-1.56 (m, 1H), 1.15 (d, J=3.2 Hz, 9H); MS (ESI) m/z 546.35 (M+H).

S20-10-2:

¹H NMR (400 MHz, CD₃OD) δ 6.76 (d, J=9.6 Hz, 1H), 4.29 (s, 2H), 4.10 (s,1H), 3.16-2.89 (m, 11H), 2.61 (t, J=14.4 Hz, 1H), 2.24-2.19 (m, 1H),2.09 (hept, J=6.4 Hz, 1H), 1.66-1.56 (m, 1H), 1.06 (d, J=6.4 Hz, 6H); MS(ESI) m/z 518.35 (M+H).

S20-10-5:

¹H NMR (400 MHz, CD₃OD) δ 6.76 (d, J=9.6 Hz, 1H), 4.28 (s, 2H), 4.11 (s,1H), 3.15-2.92 (m, 11H), 2.61 (t, J=14.6 Hz, 1H), 2.24-2.20 (m, 1H),1.72-1.56 (m, 4H), 0.98 (d, J=6.4 Hz, 6H); MS (ESI) m/z: 532.30 (M+H).

S20-10-6:

¹H NMR (400 MHz, CD₃OD) δ 6.76 (d, J=10.1 Hz, 1H), 4.29 (s, 2H), 4.10(s, 1H), 3.15-2.92 (m, 11H), 2.61 (t, J=14.6 Hz, 1H), 2.24-2.19 (m, 1H),1.67-1.56 (m, 3H), 0.98 (s, 9H); MS (ESI) m/z 546.37 (M+H).

S20-10-7:

¹H NMR (400 MHz, CD₃OD) δ 6.75 (d, J=10.1 Hz, 1H), 4.26 (s, 2H), 4.09(s, 1H), 3.53-3.47 (m, 1H), 3.12-2.91 (m, 9H), 2.60 (t, J=14.6 Hz, 1H),2.22-2.18 (m, 1H), 1.65-1.56 (m, 1H), 1.41 (d, J=6.4 Hz, 6H); MS (ESI)m/z 504.39 (M+H).

S20-10-8:

¹H NMR (400 MHz, CD₃OD) δ 6.75 (d, J=9.6 Hz, 1H), 4.26 (s, 2H), 4.10 (s,1H), 3.68-3.63 (m, 1H), 3.16-2.88 (m, 9H), 2.59 (t, J=14.6 Hz, 1H),2.23-2.14 (m, 3H), 1.87-1.68 (m, 6H), 1.64-1.55 (m, 1H); MS (ESI) m/z530.36 (M+H).

S20-10-3:

¹H NMR (400 MHz, CD₃OD) δ 6.75 (d, J=9.6 Hz, 1H), 4.23 (s, 2H), 4.10 (s,1H), 3.11-2.92 (m, 9H), 2.60 (t, J=14.2 Hz, 1H), 2.22-2.19 (m, 1H),1.64-1.55 (m, 1H), 1.48 (s, 9H); MS (ESI) m/z 518.42 (M+H).

Isobutylamine (13 μL, 0.12 mmol, 5.0 equiv), acetic acid (7 μL, 0.12mmol, 5.0 equiv) and sodium triacetoxyborohydride (11 mg, 0.050 mmol,2.0 equiv) were added sequentially to a solution of compound S20-7 (21mg, 0.025 mmol, 1.0 equiv) in 1,2-dichloroethane (0.5 mL) at 23° C.After stirring overnight, the reaction mixture was quenched by theaddition of saturated aqueous sodium bicarbonate and pH 7 phosphatebuffer (1:1, 20 mL) and extracted with dichloromethane (3×15 mL). Thecombined organic extracts were dried over anhydrous sodium sulfate,filtered, and concentrated. The residue was purified by a preparativereverse phase HPLC on a Waters Autopurification system using a SunfirePrep C18 OBD column [5 μm, 19×50 mm; flow rate, 20 mL/min; Solvent A:H2O with 0.1% HCO2H; Solvent B: CH3CN with 0.1% HCO2H; injection volume:3.0 mL (CH3CN); gradient: 20→100% B in A over 10 min; mass-directedfraction collection]. Fractions containing the desired product werecollected and concentrated to yield compound S20-8-9 (5 mg, 19%): ¹H NMR(400 MHz, CDCl3) δ 16.03 (br s, 1H), 7.49-7.48 (m, 2H), 7.38-7.30 (m,8H), 5.35 (s, 2H), 5.00 (d, J=11.0 Hz, 1H), 4.68 (d, J=11.0 Hz, 1H),3.98 (d, J=10.4 Hz, 1H), 3.70-3.61 (m, 2H), 3.38 (dd, J=4.9, 16.5 Hz,1H), 3.23 (br s, 2H), 3.02-2.97 (m, 1H), 2.57-2.44 (m, 3H), 2.50 (s,6H), 2.26-2.23 (m, 2H), 2.15 (d, J=14.6 Hz, 1H), 1.80-1.74 (m, 1H),1.65-1.52 (m, 1H), 0.98-0.93 (m, 6H), 0.83-0.80 (m, 15H), 0.28 (s, 3H),0.13 (s, 3H); MS (ESI) m/z 941.50, 943.50 (M+H).

Aqueous HF (48-50%, 0.3 mL) was added to a solution of compound S20-8-9in acetonitrile (0.8 mL) in a polypropylene reaction vessel at 23° C.The resulting mixture was stirred vigorously at 23° C. overnight andpoured into aqueous K₂HPO₄ (3.6 g dissolved in 20 mL water). Theresulting mixture was extracted with EtOAc (30 mL, then 10 mL). Thecombined organic extracts were dried over anhydrous sodium sulfate,filtered, and concentrated. The residue was dissolved in MeOH containingHCl/MeOH (0.5 N, 28 μL, 0.014 mmol, 3.0 equiv), concentrated and driedunder high vacuum. The residue was used directly in the next stepwithout further purification.

The above crude product was dissolved in MeOH (1 mL). Pd—C (10 wt %, 2mg) was added in one portion at 23° C. The reaction vessel was sealedand purged with hydrogen by briefly evacuating the flask followed byflushing with hydrogen gas (1 atm). After stirring at 23° C. for 30 min,more Pd—C (10 wt %, 3 mg) was added. The resulting mixture was stirredfor 30 min, filtered through a small Celite pad, and the filtrate wasconcentrated. The residue was purified by a preparative reverse phaseHPLC on a Waters Autopurification system using a Phenomenex Polymerx 10μRP-γ 100A column [10 μm, 150×21.20 mm; flow rate, 20 mL/min; Solvent A:0.05 N HCl/water; Solvent B: CH₃CN; injection volume: 3.0 mL (0.05 NHCl/water); gradient: 15-50% B over 15 min, then 100% B for 5 min;mass-directed fraction collection]. Fractions containing the desiredproduct, eluting at 18.2-19.0 min, were collected and freeze-dried toyield compound S20-20-9 (1 mg, 40% for 2 steps): ¹H NMR (400 MHz, CD₃OD)δ 6.19 (s, 1H), 4.23 (s, 2H), 4.05 (s, 1H), 3.13-2.77 (m, 13H), 2.47 (t,J=14.2 Hz, 1H), 2.17-1.95 (m, 3H), 1.60-1.51 (m, 1H), 1.05 (d, J=6.4 Hz,6H), 1.00 (d, J=6.4 Hz, 6H); MS (ESI) m/z 571.50 (M+H).

Example 21 Synthesis of Compounds Via Scheme 21

The following compounds were prepared according to Scheme 21.

To a white suspension of S21-1 (4.27 g, 25.40 mmol, 1.0 equiv),anhydrous acetone (4.20 mL, 57.20 mmol, 2.25 equiv), and DMAP (0.17 mg,1.38 mmol, 0.05 equiv) in DME (60 mL) at 0° C. was added SOCl₂ (5.03 mL,69.00 mmol, 2.70 equiv) dropwise. The resulting clear solution wasstirred from 0° C. to rt for 2 hrs, and slowly added into saturatedaqueous NaHCO₃ (300 mL). The mixture was extracted with EtOAc (100mL×3). The combined extracts were dried over sodium sulfate andconcentrated under reduced pressure to yield crude S21-2 as a yellowsolid: R_(f) 0.45 (40% EtOAc/hexanes); ¹H NMR (400 MHz, CDCl₃) δ 6.38(d, J=1.84 Hz, 1H), 6.25 (d, J=2.44 Hz, 1H), 2.61 (s, 3H), 1.67 (s, 6H).

To compound S21-2 (25.40 mmol, 1.0 equiv) and triethylamine (4.25 mL,30.50 mmol, 1.2 equiv) in dry dichloromethane (70 mL) at 0° C. was addedTf₂O (4.49 mL, 26.69 mmol, 1.05 equiv) dropwise. The reaction wasstirred at 0° C. for 1 hr, quenched by saturated aqueous ammoniumchloride (250 mL), and extracted with dichloromethane (100 mL×3). Thedichloromethane extracts were dried over sodium sulfate and concentratedunder reduced pressure. Flash column chromatography on silica gel with0%-5% EtOAc/hexanes yielded the desired compound S21-3 as a pale solidafter standing in a refrigerator overnight (7.23 g, 84% 2 steps): R_(f)0.33 (10% EtOAc/hexanes); ¹H NMR (400 MHz, CDCl₃) δ 6.82 (d, J=1.84 Hz,1H), 6.77 (d, J 2.44 Hz, 1H), 2.71 (s, 3H), 1.71 (s, 6H).

To compound S21-3 (3.40 g, 10.00 mmol, 1.0 equiv), t-butylcarbamate(1.76 g, 15.00 mmol, 1.5 equiv), cesium carbonate (5.86 g, 18.00 mmol,1.8 equiv), and Xantphos (0.69 g, 1.20 mmol, 0.12 equiv) in dry dioxane(50 mL) at room temperature was added Pd₂(dba)₃ (0.18 g, 0.20 mmol, 0.04equiv Pd). The mixture was purged by bubbling with dry nitrogen gas for5 min with gentle stirring. The reaction vessel was then heated undernitrogen at 80° C. for 5 hrs with rapid stirring. The resultinglight-green mixture was cooled to rt, diluted with water (200 mL), andextracted with EtOAc (200 mL×1, 50 mL×2). The EtOAc extracts were driedover sodium sulfate and concentrated under reduced pressure. Flashcolumn chromatography on silica gel with 0%-20% EtOAc/hexanes affordedthe desired product S21-4 as a pale solid (quantitative): R_(f) 0.45(20% EtOAc/hexanes); ¹H NMR (400 MHz, CDCl₃) δ 7.06 (d, J=1.80 Hz, 1H),6.72 (d, J=1.80 Hz, 1H), 6.56 (br s, 1H), 2.61 (s, 3H), 1.66 (s, 6H),1.50 (s, 9H).

Compound S21-4 (10.00 mmol, 1.0 equiv) was dissolved in dioxane (50 mL).Water (50 mL) and 6 N aqueous NaOH (8.30 mL, 50.00 mmol, 5.0 equiv) wereadded. The pale suspension was heated at 70° C. with stirring for 20hrs. The resulting clear yellow solution was cooled to 0° C., carefullyacidified with 0.5 N aqueous HCl to pH 5-6, and extracted with EtOAc(200 mL×1, 50 mL×5). The EtOAc extracts were dried over sodium sulfateand concentrated under reduced pressure to yield crude S21-5 as a palesolid (quantitative): R_(f) 0.10 (20% EtOAc/hexanes); ¹H NMR (400 MHz,CDCl₃ with 2 drops of CD₃OD) δ 6.85 (br s, 1H), 6.76 (br s, 1H), 2.51(s, 3H), 1.48 (s, 9H).

To compound S21-5 (10.00 mmol, 1.0 equiv) in dry dichloromethane wasadded phenol (1.88 g, 20.00 mmol, 2.0 equiv), DMAP (1.34 g, 11.00 mmol,1.1 equiv), and EDC (4.79 g, 25.00 mmol, 2.5 equiv). The light-yellowsolution was stirred at rt for 20 hrs, diluted with EtOAc (300 mL),washed with saturated aqueous ammonium chloride (100 mL×2), saturatedaqueous sodium bicarbonate (100 mL×2), and brine (100 mL×1). The EtOAcsolution was dried over sodium sulfate and concentrated under reducedpressure to yield crude S21-6 as a light brown oil (quantitative).

Compound S21-6 (10.00 mmol, 1.0 equiv) was dissolved in dry DMF (25 mL).Di-t-butyl dicarbonate (6.55 g, 30.00 mmol, 3.0 equiv), DIEA (6.97 mL,40.00 mmol, 4.0 equiv), and DMAP (61 mg, 0.50 mmol, 0.05 equiv) wereadded. The solution was stirred at it for 20 hrs, diluted with EtOAc(200 mL), and washed with water (250 mL×1), saturated aqueous sodiumbicarbonate (100 mL×2), and brine (100 mL×1). The EtOAc solution wasdried over sodium sulfate and concentrated under reduced pressure. Flashcolumn chromatography on silica gel with 0%-15% EtOAc/hexanes yieldedthe desired product S21-7 as a white solid (3.48 g, 64% 4 steps): R_(f)0.50 (20% EtOAc/hexanes); ¹H NMR (400 MHz, CDCl₃) δ 7.39-7.43 (m, 2H),7.22-7.26 (m, 3H), 6.96 (br s, 1H), 6.93 (d, J=1.84 Hz, 1H), 2.51 (s,3H), 1.43 (s, 18H), 1.43 (s, 9H).

To diisopropylamine (28 μL, 0.20 mmol, 2.0 equiv) in anhydrous THF (4mL) at −78° C. was added n-BuLi (0.13 mL, 1.6 M/hexanes, 0.20 mmol, 2.0equiv). The solution was stirred at 0° C. for 10 min and cooled to −78°C. TMEDA (33 μL, 0.22 mmol, 2.2 equiv) was added, followed by dropwiseaddition of compound S21-7 (0.11 g, 0.20 mmol, 2.0 equiv) in anhydrousTHF (4 mL) over a period of 5 min. Additional LDA (0.17 mL, 1.2M/heptane/THF/ethylbenzene, 0.20 mmol, 2.0 equiv) was added. Theresulting deep-red solution was stirred at −78° C. for 15 min. Enone (48mg, 0.10 mmol, 1.0 equiv) in anhydrous THF (4 mL) was added. Theresulting red-brown solution was slowly warmed to −10° C. over a periodof 1 hr, quenched by pH 7 phosphate buffer (40 mL), and extracted withEtOAc (20 mL×3). The EtOAc extracts were combined, dried over sodiumsulfate, and concentrated under reduced pressure. Flash columnchromatography on silica gel with 0%-10% EtOAc/hexanes yielded thedesired product S21-8 as a yellow foam (85 mg, 91%): R_(f) 0.45 (20%EtOAc/hexanes); ¹H NMR (400 MHz, CDCl₃) δ 15.72 (s, 1H), 7.30-7.50 (m,5H), 6.94 (d, J=1.8 Hz, 1H), 6.86 (d, J=1.8 Hz, 1H), 5.34 (s, 2H), 3.94(d, J=10.4 Hz, 1H), 2.80-3.20 (m, 2H), 2.45-2.55 (m, 10H), 1.52 (s, 9H),1.43 (s, 18H), 0.82 (s, 9H), 0.25 (s, 3H), 0.11 (s, 3H); MS (ESI) m/z932.3 (M+H), calcd for C₄₉H₆₅N₃O₁₃Si 931.4.

To compound S21-8 (82 mg, 0.088 mmol) in THF (1.5 mL) was added 50%aqueous HF (0.5 mL, 48-50%). The bright yellow solution was stirred atrt overnight, diluted with aqueous K₂HPO₄ (7.5 g in 30 mL water), andextracted with EtOAc (20 mL×3). The EtOAc extracts were combined, driedover sodium sulfate, and concentrated under reduced pressure to yieldcrude S21-9 as a yellow solid (37 mg, 81%): MS (ESI) m/z 518.3 (M+H),calcd for C₂₃H₂₇N₃O₇ 517.2.

To compound S21-9 (37 mg, 0.071 mmol, 1.0 equiv) in MeOH (7 mL) anddioxane (1 mL) was added 0.5 N HCl/MeOH (2 mL) and 10% Pd—C (30 mg,0.014 mmol, 0.20 equiv). The mixture was purged with hydrogen andstirred under 1 atm hydrogen atmosphere at rt for 1 h. The catalyst wasfiltered off with a small Celite pad, and the Celite pad was washed withMeOH (5 mL×3). The yellow MeOH solution was concentrated under reducedpressure. One half of the crude product was purified by reverse phaseHPLC using similar conditions for S2-4-1 to give the desired productS21-10 as an orange solid (9 mg, 24%, bis-HCl salt): ¹H NMR (400 MHz,CD₃OD) δ 6.17 (s, 1H), 6.12 (s, 1H), 4.03 (s, 1H), 3.03 (s, 3H), 2.97(s, 3H), 2.75-3.20 (m, 2H), 2.72 (dd, J=5.9, 14.8 Hz, 1H), 2.45 (t,J=14.3 Hz, 1H), 2.08-2.16 (m, 1H), 1.40-1.60 (m, 1H); MS (ESI) m/z 430.2(M+H), calcd for C₂₁H₂₃N₃O₇ 429.2.

To compound S21-10 (7 mg, 0.014 mmol, 1.0 equiv) in MeOH (2 mL) wasadded HCl/MeOH (0.5 mL, 0.5 N) and 10% Pd—C (5 mg, 0.0020 mmol, 0.16equiv). The mixture was purged with hydrogen and stirred under 1 atmhydrogen atmosphere at rt for 3 hrs. The catalyst was filtered off witha small Celite pad, and the Celite pad was washed with MeOH (2 mL×3).The yellow MeOH solution was concentrated under reduced pressure. HPLCpurification using similar conditions for S2-4-1 yielded the desiredproduct S21-11 as a bright yellow solid (4 mg, 47%, bis-HCl salt): ¹HNMR (400 MHz, CD₃OD) δ 4.06 (s, 1H), 3.13 (s, 6H), 3.03 (s, 3H), 2.97(s, 3H), 2.90-3.20 (m, 2H), 2.83 (dd, J=4.9, 14.6 Hz, 1H), 2.50 (t,J=14.3 Hz, 1H), 2.12-2.20 (m, 1H), 1.49-1.60 (m, 1H); MS (ESI) m/z 458.3(M+H), calcd for C₂₃H₂₇N₃O₇ 457.2.

Bromoacetyl bromide (5 μL, 0.057 mmol. 1.1 equiv) was added to compoundS21-9 (36 mg, 0.051 mmol, 1.0 equiv) in THF (2 mL) at rt. The brightyellow solution was stirred at rt for 1 h. Pyrrolidine (0.021 mL, 0.25mmol, 5.0 equiv) was added. The reaction was stirred at t for anotherhour and concentrated under reduced pressure to yield the crudeintermediate: MS (ESI) m/z 743.4 (M+H), calcd for C₄₀H₅₀N₄O₈Si 742.3.

To the above crude intermediate (0.051 mmol) in THF (1.5 mL) was added50% aqueous HF (0.5 mL, 48-50%). The bright yellow solution was stirredat rt for 4 hrs, diluted with aqueous K₂HPO₄ (7.5 g in 30 mL water), andextracted with EtOAc (30 mL×3). The EtOAc extracts were combined, driedover sodium sulfate, and concentrated under reduced pressure to yieldthe crude desilylated product as a yellow solid: MS (ESI) m 629.3 (M+H),calcd for C₃₄H₃₆N₄O₈ 628.2.

To the above crude desilylated product (0.051 mmol, 1.0 equiv) in MeOH(4 mL) was added HCl (1 mL, 0.5 N/MeOH) and 10% Pd—C (22 mg, 0.010 mmol,0.2 equiv). The mixture was purged with hydrogen and stirred under 1 atmhydrogen atmosphere at rt for 1 h. The catalyst was filtered off with asmall Celite pad, and the Celite pad was washed with MeOH (5 mL×3). Theyellow MeOH solution was concentrated under reduced pressure. HPLCpurification using similar conditions for S2-4-1 yielded the desiredproduct S21-12-1 as a bright yellow solid (17 mg, 55% 3 steps, bis-HClsalt): ¹H NMR (400 MHz, CD₃OD) δ 7.24 (s, 1H), 6.96 (s, 1H), 4.29 (s,2H), 4.09 (s, 1H), 3.75-3.85 (m, 2H), 3.15-3.28 (m, 2H), 3.05 (s, 3H),2.98 (s, 3H), 2.90-3.20 (m, 2H), 2.83 (dd, J=5.2, 15.5 Hz, 1H), 2.54 (t,J=14.3 Hz, 1H), 2.00-2.22 (m, 5H), 1.50-1.65 (m, 1H); MS (ESI) m/z 541.3(M+H), calcd for C₂₇H₃₂N₄O₈ 540.2.

Acryloyl chloride (9 μL, 0.11 mmol, 2.0 equiv) was added to compoundS21-9 (36 mg, 0.051 mmol, 1.0 equiv) in THF (2 mL) at rt. The yellowsolution was stirred at rt overnight. Pyrrolidine (0.021 mL, 0.25 mmol,5.0 equiv) was added. The reaction was stirred at rt for another hourand concentrated under reduced pressure to yield the crude intermediate:MS (ESI) m/z 757.4 (M+H), calcd for C₄₁H₅₂N₄O₈Si 756.4.

The crude intermediate was treated with aqueous HF followed byhydrogenation under similar conditions to that in the preparation ofcompound S21-12-1 to yield the desired product S21-12-2 as abright-yellow solid (17 mg, 53% 3 steps, bis-HCl salt): ¹H NMR (400 MHz,CD₃OD) δ 7.24 (s, 1H), 6.95 (s, 1H), 4.06 (s, 1H), 3.65-3.75 (m, 2H),3.54 (t, J=8.0 Hz, 2H), 3.10-3.20 (m, 2H), 2.80-3.20 (m, 10H), 2.80 (dd,J=5.3, 18.7 Hz, 1H), 2.53 (t, J=14.0 Hz, 1H), 2.10-2.22 (m, 3H),2.00-2.10 (m, 2H), 1.50-1.63 (m, 1H); MS (ESI) m/z 555.3 (M+H), calcdfor C₂₈H₃₄N₄O₈ 554.2.

N-Methyl morpholine (0.028 mL, 0.25 mmol, 15 equiv),chloroethanesulfonyl chloride (0.027 mL, 0.25 mmol, 15 equiv), and DMAP(2 mg, 0.017 mmol, 1.0 equiv) were added to compound S21-9 (12 mg, 0.017mmol, 1.0 equiv) in THF (2 mL) at rt. The reaction was stirred at rt for72 hrs. Pyrrolidine (0.071 mL, 0.85 mmol, 50 equiv) was added. Thereaction was stirred at rt for 30 min. Aqueous HF (2 mL, 48-50%) wasadded. The reaction was stirred at rt overnight. The yellow solution wasdiluted with aqueous K₂HPO₄ (20 g in 80 mL water) and extracted withEtOAc (30 mL×3). The EtOAc extracts were combined, dried over sodiumsulfate, and concentrated under reduced pressure to yield the crudedeisilylated sulfonamide: MS (ESI) m/z 679.3 (M+H), calcd forC₄₃H₃₈N₄O₉S 678.2.

The above crude product (0.017 mmol, 1.0 equiv) was dissolved in MeOH (3mL) and dioxane (1 mL). HCl/MeOH (1 mL, 0.5 N) and 10% Pd—C were added.The mixture was purged with hydrogen and stirred under 1 atm hydrogenatmosphere at rt for 3 hrs. The catalyst was filtered off with a smallCelite pad, and the Celite pad was washed with MeOH (2 mL×3). The MeOHfiltrate was concentrated under reduced pressure. HPLC purificationusing similar conditions for S2-4-1 yielded the desired product S21-12-3as a bright-yellow solid (3 mg, 27% 3 steps, bis-HCl salt): ¹H NMR (400MHz, CD₃OD) δ 6.03 (s, 1H), 5.92 (s, 1H), 4.02 (s, 1H), 3.63 (t, J=7.0Hz, 2H), 2.80-3.40 (m, 8H), 3.02 (s, 3H), 2.96 (s, 3H), 2.70 (dd, J=4.9,14.7 Hz, 1H), 2.41 (t, J=13.7 Hz, 1H), 1.85-1.95 (m, 4H), 1.45-1.60 (m,1H); MS (ESI) m/z 591.3 (M+H), calcd for C₂₇H₃₄N4O₉S 590.2.

To a suspension of S21-9 (35 mg, 0.056 mmol, 1.0 equiv) indichloromethane (0.22 mL) was added pyridine (14 μL, 0.17 mmol, 3.0equiv) and methanesulfonyl chloride (5 μL, 0.061 mmol, 1.1 equiv). Theheterogeneous mixture was stirred at room temperature for 21 hrs, andwas concentrated under reduced pressure to remove solvent and excesspyridine. This crude mixture was then dissolved in dioxane (1.2 mL) in aplastic vial. A queous HF (0.3 mL, 48-50%) was then added and thereaction was stirred at room temperature for 19 hrs. The reactionmixture was poured into an aqueous solution of K₂HPO₄ (3.6 g in 30 mL)and was extracted with EtOAc (2×25 mL). The combined organic layers weredried over sodium sulfate, were filtered, and were concentrated underreduced pressure to provide an orange oil. This oil was dissolved inMeOH/dioxane (1 mL, 1:1) and Pd—C (10 mg, 10 wt %) was added. Thereaction was purged with hydrogen and stirred under hydrogen (balloon)at room temperature for 22 hrs. The reaction mixture was filteredthrough a small Celite plug and the filtrate was concentrated underreduced pressure. The crude product was purified via preparative reversephase HPLC on a Waters Autopurification system using a PhenomenexPolymerx p RP-γ 100A column [10 μm, 150×21.20 mm; flow rate, 20 mL/min;Solvent A: 0.05 N HCl/water; Solvent B: CH₃CN; injection volume: 2.2 mL(0.05 N HCl/water); gradient: 0→70% B over 15 min; mass-directedfraction collection]. Fractions containing the desired product, elutingat 8.9-9.7 min, were collected and freeze-dried to yield 3 mg ofcompound S21-12-4 as a yellow solid (12% for 3 steps): ¹H NMR (400 MHz,CD₃OD) δ 6.63-6.61 (m, 1H), 6.58 (br s, 1H), 4.04 (s, 1H), 3.10-2.89 (m,8H), 2.79 (dd, J=15.3, 4.3 Hz, 1H), 2.52 (t, J=14.7 Hz, 1H), 2.19-2.09(m, 1H), 1.63-1.48 (m, 1H); MS (ESI) m/z 508.24 (M+H).

To a suspension of S21-9 (35 mg, 0.056 mmol, 1.0 equiv) indichloromethane (0.22 mL) was added pyridine (14 μL, 0.17 mmol, 3.0equiv) and benzenesulfonyl chloride (8 μL, 0.061 mmol, 1.1 equiv). Theheterogeneous mixture was stirred at room temperature for 21 hrs and wasconcentrated under reduced pressure to remove solvent and excesspyridine. This crude mixture was then dissolved in dioxane (1 mL) in aplastic vial. A queous HF (0.25 mL, 48-50%) was added and the reactionmixture was stirred at room temperature for 3 hrs. The reaction mixturewas poured into an aqueous solution of K₂HPO₄ (3.0 g in 25 mL) and wasextracted with EtOAc (2×25 mL). The combined organic layers were driedover sodium sulfate, were filtered, and were concentrated under reducedpressure to provide an orange oil. This oil was dissolved inMeOH/dioxane (1 mL, 1:1) and Pd—C (10 mg, 10 wt %) was added. Thereaction was purged with hydrogen and stirred under hydrogen (balloon)at room temperature for 17 hrs. The reaction mixture was filteredthrough a small Celite plug and the filtrate was concentrated underreduced pressure. The crude product was purified via preparative reversephase HPLC on a Waters Autopurification system using a PhenomenexPolymerx RP-γ 100A column [10 μm, 150×21.20 mm; flow rate, 20 mL/min;Solvent A: 0.05 N HCl/water; Solvent B: CH₃CN; injection volume: 3.8 mL(0.05 N HCl/water); gradient: 20→70% B over 15 min; mass-directedfraction collection]. Fractions containing the desired product, elutingat 9.0-10.1 min, were collected and freeze-dried to yield 4 mg ofcompound S21-12-5 as a yellow solid (13% for 3 steps):

¹H NMR (400 MHz, CD₃OD) δ 7.90-785 (m, 2H), 7.63-7.57 (m, 1H), 7.56-7.49(m, 2H), 6.56-6.53 (m, 1H), 6.48 (br s, 1H), 3.99 (s, 1H), 3.01-2.83 (m,8H), 2.69 (dd, J=15.3, 4.3 Hz, 1H), 2.43 (t, J=14.6 Hz, 1H), 2.15-2.06(m, 1H), 1.59-1.46 (m, 1H); MS (ESI) m/z 570.25 (M+H).

To a suspension of S21-9 (34 mg, 0.053 mmol, 1.0 equiv) indichloromethane (0.22 mL) was added trimethylacetylchloride (7 μL, 0.058mmol, 1.1 equiv). The mixture was heterogeneous after 2 hrs and thereaction was complete after 4 hrs. The reaction mixture was concentratedunder reduced pressure. The residue was redissolved in dioxane (1.2 mL)in a plastic vial. A queous HF (0.25 mL, 48-50%) was added and thereaction mixture was stirred at room temperature for 13 hrs. Thereaction mixture was poured into an aqueous solution of K₂HPO₄ (3.1 g in25 mL) and was extracted with EtOAc (2×25 mL). The combined organiclayers were dried over sodium sulfate, were filtered, and wereconcentrated under reduced pressure to provide an orange oil. This oilwas dissolved MeOH/dioxane (1 mL, 1:1) and Pd—C (10 mg, 10 wt %) wasadded. The reaction was purged with hydrogen and stirred under hydrogen(balloon) at room temperature for 2 hrs. The reaction mixture wasfiltered through a small Celite plug and the filtrate was concentratedunder reduced pressure. The crude product was purified via preparativereverse phase HPLC on a Waters Autopurification system using aPhenomenex Polymerx p RP-γ 100A column [10 μm, 150×21.20 mm; flow rate,20 mL/min; Solvent A: 0.05 N HCl/water; Solvent B: CH₃CN; injectionvolume: 2.2 mL (0.05 N HCl/water); gradient: 20→70% B over 15 min;mass-directed fraction collection]. Fractions containing the desiredproduct, eluting at 8.0-9.5 min, were collected and freeze-dried toyield 15 mg of compound S21-12-6 as a yellow solid (53% for 3 steps): ¹HNMR (400 MHz, CD₃OD) δ 7.18 (d, J=1.93, 1H), 7.04 (br s, 1H), 4.06 (s,1H), 3.11-2.88 (m, 8H), 2.76 (dd, J=15.3, 4.2 Hz, 1H), 2.51 (t, J=14.0Hz, 1H), 2.20-2.12 (m, 1H), 1.62-1.49 (m, 1H), 1.27 (s, 9H); MS (ESI)m/z 514.32 (M+H).

Example 22 Synthesis of Compounds Via Scheme 22

The following compounds were prepared according to Scheme 22.

Compound S21-3 (1.02 g, 3.00 mmol, 1.0 equiv) was dissolved in dry1,4-dioxane (20 mL). 4-Aminopyridine (0.42 g, 4.50 mmol, 1.5 equiv),cesium carbonate (1.76 g, 5.40 mmol, 1.8 equiv), Xantphos (0.21 g, 0.36mmol, 0.12 equiv), and Pd₂(dba)₃ (55 mg, 0.060 mmol, 0.02 equiv) wereadded. The mixture was purged with dry nitrogen, heated at 80° C. withvigorous stirring for 2 hrs, cooled to rt, diluted with water (100 mL),and extracted with EtOAc (100 mL×1, 20 mL×2). The EtOAc extracts werecombined, dried over sodium sulfate, and concentrated under reducedpressure. Flash column chromatography on silica gel with 50%EtOAc/hexanes, 100% EtOAc/hexanes, and 10% MeOH/dichloromethane yieldedthe desired product S22-1 as a pale solid (0.613 g, 72%): R_(f)=0.17 10%MeOH/dichloromethane; ¹H NMR (400 MHz, CD₃OD) δ 8.30 (d, J=6.7 Hz, 2H),6.98 (d, J=6.7 Hz, 2H), 6.58 (s, 2H), 2.60 (s, 3H), 1.66 (s, 6H); MS(ESI) m/z 285.0 (M+H), calcd for C₁₆H₆N₂O₃ 284.1.

Compound S22-1 (0.55 g, 1.93 mmol, 1.0 equiv) was dissolved in dioxane(9 mL) and water (7.4 mL). Aqueous NaOH (1.61 mL, 6 N, 9.66 mmol, 5.0equiv) was added. The suspension was heated at 70° C. with stirringovernight, cooled to rt, neutralized with 6 N aqueous HCl to pH 6-7. Theprecipitates were collected, washed with water (2 mL×3) and ethanol (2mL×3), and dried under reduced pressure to yield the desired compoundS22-2 as a pale solid (quantitative): ¹H NMR (400 MHz, CD₃OD) δ 8.15 (d,J=7.3 Hz, 2H), 7.15 (d, J=7.3 Hz, 2H), 6.59 (d, J=1.8 Hz, 1H), 6.53 (d,J=1.8 Hz, 1H), 2.61 (s, 3H); MS (ESI) m/z 245.0 (M+H), calcd forC₁₃H₁₂N₂O₃ 244.1.

Compound S22-2 (0.57 g, 2.34 mmol, 1.0 equiv) was dissolved indichloromethane (50 mL). Phenol (0.44 g, 4.68 mmol, 2.0 equiv), DMAP(0.32 g, 2.58 mmol, 1.1 equiv), DIEA (1.22 mL, 7.00 mmol, 3.0 equiv),and EDC (1.12 g, 5.84 mmol, 2.5 equiv) were added. The solution wasstirred at rt for 48 hrs. Most of the dichloromethane was removed underreduced pressure. The residue was re-dissolved in EtOAc (100 mL), washedwith water (100 mL×2), saturated aqueous sodium bicarbonate (50 mL×2)and brine (50 mL×1), dried over sodium sulfate, and concentrated underreduced pressure to yield the crude phenyl ester as a pale foam.

The above crude phenyl ester was dissolved in dry DMF (10 mL).Di-t-butyl dicarbonate (1.66 g. 7.61 mmol, 3.0 equiv), DIEA (1.77 mL,10.16 mmol, 4.0 equiv), and DMAP (16 mg, 0.13 mmol, 0.05 equiv) wereadded. The reaction was stirred at rt for 24 hrs. More di-t-butyldicarbonate (0.60 g) and DIEA (0.60 mL) were added. Stirring wascontinued at rt for another 24 hrs. The deep red reaction solution wasdiluted with EtOAc (100 mL), washed with water (200 mL×1), saturatedaqueous sodium bicarbonate (100 mL×2) and brine (100 mL×1), dried oversodium sulfate, and concentrated under reduced pressure. Flash columnchromatography on silica gel with 0% to 5% MeOH/dichloromethane yieldedthe desired product S22-3 as a light-yellow foam (0.18 g, 13%):R_(f)=0.80 (10% MeOH/dichloromethane); ¹H NMR (400 MHz, CDCl₃) δ 8.49(d, J=6.1 Hz, 2H), 7.40-7.45 (m, 2H), 7.20-7.30 (m, 3H), 7.15 (d, J=6.1Hz, 2H), 6.95 (s, 1H), 6.90 (s, 1H), 2.49 (s, 3H), 1.46 (s, 9H), 1.42(s, 9H); MS (ESI) m/z 521.3 (M+H), calcd for C₂₉H₃₂N₂O₇ 520.2.

To diisopropylamine (0.053 mL, 0.37 mmol, 2.2 equiv) in anhydrous THF (5mL) at −78° C. was added n-BuLi (0.24 mL, 1.6 M/hexanes, 0.38 mmol, 2.2equiv). The pale solution was stirred at 0° C. for 10 min and cooled to−78° C. TMEDA (0.062 mL, 0.41 mmol, 2.4 equiv) was added, followed bydropwise addition of a solution of compound S22-3 (0.18 g, 0.34 mmol,2.0 equiv) in THF (4 mL) over a period of 10 min. Additional LDA (0.38mmol, 2.2 equiv) was added. The deep red solution was stirred at −78° C.for 15 min. Enone S1-9 (82 mg, 0.017 mmol, 1.0 equiv) in THF (5 mL) wasadded dropwise over a period of 5 min. The red solution was slowlywarmed to −10° C. over a period of 1 h, quenched by pH 7 phosphatebuffer (1 M, 50 mL), and extracted with EtOAc (20 mL×3). The EtOAcextracts were combined, dried over sodium sulfate, and concentratedunder reduced pressure. Flash column chromatography on silica gel with0% to 2% MeOH/dichloromethane yielded the desired product S22-4 as ayellow oil (0.20 g, ˜80% pure): MS (ESI) m/z 909.3 (M+H), calcd forC₄₉H₆₀N₄O₁₁Si 908.4.

Compound S22-4 (0.17 mmol) in dioxane (5 mL) was added with 4 NHCl/dioxane (5 mL). The reaction was stirred at rt overnight andconcentrated under reduced pressure. The residue was partitioned betweenaqueous sodium bicarbonate (50 mL) and EtOAc (50 mL). The aqueous layerwas extracted with more EtOAc (20 mL×3). The combined organic layerswere dried over sodium sulfate and concentrated under reduced pressure.Flash column chromatography on silica gel with 0%/o to 10°%/MeOH/dichloromethane yielded the desired product S22-5 as a yellowsolid (62 mg, 51% 2 steps): ¹H NMR (400 MHz, CDCl₃) δ 14.06 (br s, 1H),12.03 (s, 1H), 11.43 (s, 1H), 7.17-7.50 (m, 8H), 6.95-7.05 (m, 3H), 5.35(s, 2H), 3.89 (d, J=9.8 Hz, 1H), 3.00-3.10 (m, 1H), 2.7-2.95 (m, 2H),2.40-2.55 (m, 2H), 2.46 (s, 6H), 2.00-2.10 (m, 1H), 0.84 (s, 9H), 0.28(s, 3H), 0.14 (s, 3H); MS (ESI) m/z 709.4 (M+H), calcd for C₃₉H₄₄N₄O₇Si708.3.

Compound S22-5 (15 mg, 0.021 mmol) was treated with aqueous HF followedby hydrogenation under similar conditions to that in the preparation ofcompound S21-12-1 to yield the desired product S22-6 as a bright-yellowsolid (6 mg, 46% 2 steps, tris-HCl salt): ¹H NMR (400 MHz, CD₃OD) δ 8.30(d, J=7.3 Hz, 2H), 7.38 (d, J=7.3 Hz, 2H), 6.80 (s, 1H), 6.76 (s, 1H),4.10 (s, 1H), 2.85-3.50 (m, 3H), 3.05 (s, 3H), 2.98 (s, 3H), 2.55-2.65(m, 1H), 2.15-2.25 (m, 1H), 1.55-1.65 (m, 1H); MS (ESI) m/z 507.1 (M+H),calcd for C₂₆H₂₆N₄O₇ 506.2.

Compound S22-5 (15 mg, 0.021 mmol, 1.0 equiv) was dissolved indichloromethane. DIEA (0.030 mL, 0.17 mmol, 8.0 equiv) and aceticanhydride (7μ, 0.069 mmol, 3.5 equiv) were added in three equal portionsover a period of 4 days at rt. MeOH (1 mL) was added. The yellowsolution was concentrated under reduced pressure. HPLC purificationusing similar conditions for S2-4-1 yielded the desired product S22-7-1as a yellow solid (7 mg, 44%): ¹H NMR (400 MHz, CDCl₃) δ 15.82 (br s,1H), 8.32 (br d, J=5.5 Hz, 2H), 7.40-7.50 (m, 2H), 7.30-7.40 (m, 3H),7.05 (br d, J=5.5 Hz, 2H), 6.90 (s, 1H), 6.76 (s, 1H), 5.34 (s, 2H),3.89 (d, J=10.4 Hz, 1H), 3.00-3.10 (m, 1H), 2.75-2.95 (m, 2H), 2.35-2.55(m, 2H), 2.45 (s, 6H), 2.30 (s, 3H), 2.00-2.10 (m, 1H), 0.83 (s, 9H),0.26 (s, 3H), 0.12 (s, 3H); MS (ESI) m/z 751.4 (M+H), calcd forC₄₁H₄₆N₄O₈Si 750.3.

Compound S22-7-1 (7 mg, 0.0090 mmol) was treated with aqueous HFfollowed by hydrogenation under similar conditions to that in thepreparation of compound S21-12-1 to yield the desired product S22-8-1 asa yellow solid (3 mg, 54% 2 steps, bis-HCl salt): ¹H NMR (400 MHz,CD₃OD) δ 8.31 (d, J=7.4 Hz, 2H), 7.40 (d, J=7.3 Hz, 2H), 6.80 (s, 1H),6.78 (s, 1H), 4.37 (s, 1H), 2.70-3.50 (m, 9H), 2.55-2.65 (m, 1H),2.30-2.40 (m, 1H), 2.11 (s, 3H), 1.75-1.80 (m, 1H); MS (ESI) m/z 549.1(M+H), calcd for C₂₈H₂₈N₄O₈ 548.2.

Example 23 Synthesis of Compounds Via Scheme 23

The following compounds were prepared according to Scheme 23.

To a solution of S1-4 (8.40 g, 34.10 mmol, 1.0 equiv) in acetonitrile(41 mL) in a vial was added N-chlorosuccinimide (5.05 g, 37.80 mmol, 1.1equiv). The vial was sealed and heated to 80° C. for 2 h. The reactionmixture was concentrated under reduced pressure, then diluted with water(25 mL) and extracted with EtOAc (2×75 mL). The combined organic layerswere washed sequentially with saturated aqueous sodium bicarbonatesolution (2×20 mL), water (20 mL), and brine (20 mL). The combinedorganic layers were then dried over sodium sulfate, filtered, andconcentrated under reduced pressure. The resulting crude oil wasdissolved in acetone (70 mL). To this solution was added potassiumcarbonate (9.448 g, 68.40 mmol, 2.0 equiv) and benzyl bromide (4.89 mL,40.90 mmol, 1.2 equiv). The reaction was stirred at room temperature for17 hrs. The resulting slurry was filtered through Celite, concentratedunder reduced pressure, and purified by flash column chromatography(Biotage 340 g column, 2% to 10% EtOAc in hexanes gradient) to provideS23-1 as a colorless oil (7.31 g, 58%): ¹H NMR (400 MHz, CDCl₃) δ57.49-7.44 (m, 2H), 7.40-7.32 (m, 5H), 7.29-7.21 (m, 2H), 7.06-7.00 (3,2H), 5.10 (s, 2H), 2.34 (d, J=1.8 Hz, 3H); MS (ESI) m/z 369.13 (M−H).

LDA/THF was prepared by adding n-BuLi (1.6 M, 1.31 mL, 2.10 mmol, 1.5equiv) to diisopropylamine (0.30 mL, 2.10 mmol) in THF (5 mL) at −78° C.The reaction mixture was warmed to −20° C. and stirred for 10 min. Afterthe LDA solution was cooled to −78° C., compound S23-1 (0.52 g, 1.40mmol) in THF (2 mL) was added dropwise, forming an orange-red solution.After 10 min, a solution of iodine (0.76 g, 2.97 mmol, 2.1 equiv) in THF(2 mL) was added dropwise to the above reaction mixture. The reactionsolution was allowed to warm to −15° C. in 1 h and quenched by saturatedaqueous NH₄Cl. LC/MS indicated that the starting material was allconsumed. The reaction mixture was diluted with EtOAc (100 mL), washedwith a 5% sodium thiosulfate solution (2×30 mL), water and brine, driedover sodium sulfate, filtered, and concentrated under reduced pressure.The resulting crude oil was purified by flash column chromatography(Silicycle 12 g column, 1% to 5% EtOAc in hexanes gradient), to provideS23-2 (0.56 g, 800/%): ¹H NMR (400 MHz, CDCl₃) δ 7.48-7.43 (m, 2H),7.39-7.32 (m, 5H), 7.28-7.22 (m, 1H), 7.05-6.99 (m, 2H), 5.08 (s, 2H),2.39 (d, J=2.4 Hz, 3H); MS (ESI) m/z 495.03 (M−H).

A vial charged with S23-2 (47 mg, 0.095 mmol, 1.0 equiv),tris-(dibenzylideneacetone)dipalladium(0) (4 mg, 0.0047 mmol, 0.05equiv), Xantphos (11 mg, 0.018 mmol, 0.19 equiv), and cesium carbonate(95 mg, 0.029 mmol, 3.0 equiv) was fitted with a septum, and evacuatedand back-filled with nitrogen three times. Dioxane (0.50 mL) andpyrrolidine (0.040 mL, 0.48 mmol, 5.0 equiv) were added and the mixturewas degassed by bubbling nitrogen through the heterogeneous solution fortwo minutes. The mixture was heated at 80° C. with stirring for 2 hrs.The reaction mixture was cooled to rt, filtered through Celite, andconcentrated under reduced pressure. The resulting oil was purified byflash column chromatography (Silicycle 4 g column, 1% to 5% EtOAc inhexanes gradient), to provide compound S23-3-1 (23 mg, 55%): ¹H NMR (400MHz, CDCl₃) δ 7.52-7.46 (m, 2H), 7.40-7.30 (m, 5H), 7.27-7.22 (m, 1H),7.08-7.03 (m, 2H), 5.10 (s, 2H), 3.50-3.41 (m, 4H), 2.34 (d, J=2.4 Hz,3H), 2.00-1.90 (m, 4H); MS (ESI) m/z 440.15 (M+H).

To a solution of LDA (20.053 mL, 2.0 M/THF/heptane/ethylbenzene, 0.10mmol, 2.5 equiv) in THF (1 mL) at −70° C. was added TMEDA (0.016 mL,0.10 mmol, 2.5 equiv). A solution of compound S23-3-1 (23 mg, 0.052mmol, 1.25 equiv) in THF (0.5 mL) was added dropwise. The reaction wasstirred at −70° C. for 1 h. A solution of enone S1-9 (21 mg, 0.043 mmol,1.0 equiv) in THF (0.5 mL) was added dropwise to the reaction mixture.The reaction was stirred from −70° C. to −20° C. over 50 minutes,quenched by saturated aqueous NH₄Cl, and extracted with EtOAc (2×30 mL).The combined organic extracts were dried over sodium sulfate andconcentrated under reduced pressure. The crude product was purified bypreparative reverse phase HPLC on a Waters Autopurification system usinga Sunfire Prep C18 OBD column [5 μm, 19×50 mm; flow rate, 20 mL/min;Solvent A: H₂O with 0.1% HCO₂H; Solvent B: CH₃CN with 0.1% HCO₂H;gradient: 90-100% B over 20 min; mass-directed fraction collection].Fractions containing the desired product, eluting at 8.0-8.75 min, werecollected and freeze-dried to give 10 mg of pure compound S23-4-1 (24%):¹H NMR (400 MHz, CDCl₃) δ 16.2 (s, 1H), 7.59-7.54 (m, 2H), 7.51-7.46 (m,2H), 7.40-7.29 (m, 6H), 5.35 (s, 2H), 4.94 (d, J=9.8 Hz, 1H), 4.89 (d,J=9.8 Hz, 1H), 3.95 (d, J=10.4 Hz, 1H), 3.75-3.65 (m, 2H), 3.59-3.50 (m,2H), 3.23-3.15 (m, 1H), 3.00-2.88 (m, 1H), 2.55-2.30 (m, 9H), 2.14-2.07(m, 1H), 1.99-1.83 (m, 4H), 0.81 (s, 9H), 0.26 (s, 3H), 0.11 (s, 3H); MS(ESI) m/z 828.30 (M+H).

A solution of compound S23-4-1 (10 mg, 0.012 mmol) in 1,4-dioxane (1.3mL) was treated with HF (0.20 mL, 48-50% aqueous solution). Afterstirring overnight, the mixture was poured into a solution of K₂HPO₄(2.4 g) in water (25 mL) and extracted with EtOAc (2×30 mL). Thecombined extracts were dried over sodium sulfate, filtered, andconcentrated under reduced pressure.

The above crude material was dissolved in MeOH (0.3 mL), 1,4-dioxane(0.5 mL), and 0.5 N HCl/MeOH (0.2 mL). 10% Pd—C (Degussa, 5 mg) wasadded, and an atmosphere of hydrogen was introduced. After 17 hrs, thereaction mixture was filtered through Celite and concentrated underreduced pressure. The crude product was purified by preparative reversephase HPLC on a Waters Autopurification system using a Polymerx 10μ RP-γ100 R column [30×21.20 mm, 10 micron, solvent A: 0.05 N HCl, solvent B:CH₃CN, gradient elution with 15-80% B over 10 min, then 80-100% over 2min, held at 100% for 2 min; mass-directed fraction collection].Fractions containing the desired product, eluting at 9.9-11.2 min, werecollected and freeze-dried to yield 1 mg of compound S23-5-1 (27%): ¹HNMR (400 MHz, CD₃OD) δ 5.94 (d, J=7.3 Hz, 1H), 4.03 (s, 1H), 3.56-3.49(m, 4H), 3.13-2.84 (m, 9H), 2.20-2.09 (m, 2H), 2.03-1.91 (m, 4H),1.63-1.50 (m, 1H); MS (ESI) m/z 502.24 (M+H).

Example 24 Synthesis of Compounds Via Scheme 24

The following compounds were prepared according to Scheme 24.

BBr₃ solution in DCM (1.0 M, 27.96 mL, 27.96 mmol, 1.0 equiv) was addedto a solution of the above phenyl ester S15-5 (8.98 g, 27.96 mmol, 1.0equiv) in DCM (100 mL) at −78° C. The resulting reaction mixture wasstirred at that temperature for 20 min and at 0° C. for 15 min.Saturated NaHCO₃ solution (120 mL) was added slowly. The resultingmixture was stirred at rt for 20 min and DCM was evaporated. The residuewas extracted with ethyl acetate (250 mL). The organic was separated anddried over anhydrous MgSO₄. The dried solution was filtered, and thefiltrate was concentrated to afford an off-white solid. The residue waspurified by recrystallization from EtOAc/Hexanes to give the desiredproduct S24-1 as a white solid (6.76 g), and the mother liquor wasconcentrated and purified by flash-column chromatography (2-10% ethylacetate-hexanes) to afford additional product (973 mg) (90% yieldtotally).

¹H NMR (400 MHz, CDCl₃) δ 11.13 (s, 1H), 7.47-7.43 (m, 2H), 7.33-7.29(m, 1H), 7.19-7.16 (m, 2H), 7.08 (d, J=1.8 Hz, 1H), 6.96 (d, J=1.8 Hz,1H), 2.66 (s, 3H); MS (ESI) m/z 305.05, 307.05 (M−H).

A solution of PhI(OAc)₂ (3.77 g, 11.72 mmol, 2.1 equiv) in MeOH (20 mL)was added slowly to a solution of S24-1 (1.71 g, 5.58 mmol, 1.0 equiv)in a mixture of MeOH (30 mL) and dioxane (10 mL) at 0° C. The reactionmixture was then stirred at rt for 17 h. HOAc (6 mL) was added to thereaction mixture. Then Zn dust (1.09 g, 16.74 mmol, 3.0 equiv) was added(slightly exothermic). The resulting reaction mixture was stirred at rtfor 20 min, and filtered through a pad of Celite. The cake was washedwith EtOAc (100 mL) thoroughly. The filtrate was concentrated. Theresidue was partitioned between EtOAc (120 mL) and sat. NaHCO₃/brinesolution. (The aqueous layer pH was adjusted to 7). The organic layerwas separated and dried (MgSO₄). The dried solution was filtered, andthe filtrate was concentrated. The residue was purified by flash-columnchromatography (0-4% ethyl acetate-hexanes) to afford the desiredproduct S24-2 (763 mg, 41%). ¹H NMR (400 MHz, CDCl₃) δ 10.70 (s, 1H),7.47-7.43 (m, 2H), 7.33-7.30 (m, 1H), 7.20-7.17 (m, 2H), 7.16 (s, 1H),3.75 (s, 3H), 2.67 (s, 3H); MS (ESI) m/z 335.11, 337.14 (M−H).

Di-tert-butyl dicarbonate (543 mg, 2.49 mmol, 1.1 equiv) andN,N-dimethylaminopyridine (28 mg, 0.226 mmol, 0.1 equiv) were added to asolution of phenol S24-2 (763 mg, 2.26 mmol, 1.0 equiv) in methylenechloride (20 mL). The resulting mixture was stirred for 20 min at rt(monitored by LC-MS and TLC (product is slightly more polar)), andconcentrated. The residue was purified by flash-column chromatography(0-5% ethyl acetate-hexanes) to afford the Boc protection product S24-3as a white solid (783 mg, 79%). ¹H NMR (400 MHz, CDCl₃) δ 7.45-7.41 (m,2H), 7.38 (s, 1H), 7.30-7.26 (m, 1H), 7.24-7.22 (m, 2H), 3.81 (s, 3H),2.47 (s, 3H), 1.43 (s, 9H); MS (ESI) m/z 435.14, 437.15 (M−H).

A solution of ^(i)PrMgCl.LiCl in THF (1.2 M, 547 μL, 0.657 mmol, 2.0equiv) was added dropwise to a solution of compound S24-3 (143.6 mg,0.328 mmol, 1.0 equiv) in THF (3.3 mL) at 0° C. The resulting yellowreaction mixture was then stirred at that temperature for 1 h. Then DMF(127 μL, 1.64 mmol, 5.0 equiv) was added at 0° C. The resulting mixturewas stirred at 0° C. for 10 min and then at rt for 20 min. Sat. NH₄Cland brine were added. The resulting mixture was extracted with EtOAc (50mL). The organic layer was separated and dried (MgSO₄). The driedsolution was filtered, and the filtrate was concentrated. The crudeproduct S24-4 was used directly for the next step. ¹H NMR (400 MHz,CDCl₃) δ 10.38 (s, 1H), 7.61 (s, 1H), 7.46-7.42 (m, 2H), 7.32-7.28 (m,1H), 7.26-7.24 (m, 2H), 3.91 (s, 3H), 2.46 (s, 3H), 1.45 (s, 9H); MS(ESI) m/z 385.24 (M−H).

Trimethyl orthoformate (180 μL, 1.64 mmol, 5.0 equiv) and p-TSA (3.1 mg,0.016 mmol, 0.05 equiv) were added to a solution of the above crudeproduct S24-4 in MeOH (1 mL). The resulting reaction mixture was heatedat reflux for 1 h, and cooled to rt. The solvent was evaporated and theresidue was diluted with EtOAc (40 mL) and sat. NaHCO₃/brine solution(1:1, 20 mL). The organic phase was separated and dried (MgSO₄). Thedried solution was filtered, and the filtrate was concentrated to affordan organe oil. The crude ¹H NMR (CDCl₃) showed desired product 6 anddeBoc product (˜3:1). The crude products were used directly for the nextstep.

The above crude material was dissolved in DCM (1 mL). Di-tert-butyldicarbonate (26.8 mg, 0.123 mmol) and N,N-dimethylaminopyridine (1 mg,0.08 mmol) were added. The resulting mixture was stirred for 40 min atrt and concentrated. The residue was purified by flash-columnchromatography (2-10% ethyl acetate-hexanes) to afford the desiredproduct S24-5 as a colorless oil (124.2 mg, 87% over 3 steps). ¹H NMR(400 MHz, CDCl₃) δ 7.45-7.41 (m, 2H), 7.33 (s, 1H), 7.30-7.24 (m, 3H),5.65 (s, 1H), 3.79 (s, 3H), 3.36 (s, 6H), 2.43 (s, 3H), 1.43 (s, 9H); MS(ESI) m/z 431.29 (M−H).

nBuLi solution (2.5 M in hexanes, 138 μL, 0.345 mmol, 1.2 equiv) wasadded dropwise to a solution of diisopropylamine (49 μL, 0.345 mmol, 1.2equiv) and TMEDA (103 μL, 0.689 mmol, 2.4 equiv) in THF (2.5 mL) at −78°C. The resulting reaction solution was stirred at −78° C. for 30 min. Asolution of ester S24-5 (124.2 mg, 0.287 mmol, 1.0 equiv) in THF (1.5mL) was added via cannula. The resulting dark red solution was thenstirred at −78° C. for 30 min, and cooled to −100° C. using aEtOH/liquid N₂ bath. A solution of enone (125 mg, 0.258 mmol, 0.9 equiv)in THF (1.5 mL) was added to the reaction mixture via cannula. Theresulting reaction mixture was allowed to warm up to −78° C. over 30min. LHMDS solution (1.0 M, 287 μL, 0.287 mmol, 1.0 equiv) was added.Then the reaction mixture was warmed up to −10° C. naturally over 40min, quenched with saturated NH₄Cl and pH=7 buffer (1:1, 30 mL), andextracted with EtOAc (40 mL). The organic phase was separated, dried(Na₂SO₄), filtered and concentrated. The residue was purified byflash-column chromatography (5-30% ethyl acetate-hexanes) to afford thedesired product S24-6 as a pale yellow solid (201.6 mg, 95%). ¹H NMR(400 MHz, CDCl₃) δ 15.67 (s, 1H), 7.49-7.46 (m, 2H), 7.38-7.29 (m, 3H),5.59 (s, 1H), 5.35, 5.32 (ABq, J=12.2 Hz, 2H), 3.97 (d, J=10.4 Hz, 1H),3.73 (s, 3H), 3.37 (s, 3H), 3.31 (s, 3H), 3.28 (dd, J=4.9, 15.9 Hz, 1H),3.02-2.95 (m, 1H), 2.55-2.42 (m, 9H), 2.13 (d, J=12.0 Hz, 1H), 1.51 (s,9H), 0.82 (s, 9H), 0.25 (s, 3H), 0.11 (s, 3H); MS (ESI) m/z 821.51(M+H).

Compound S24-6 (201.6 mg, 0.246 mmol, 1.0 equiv) was dissolved in apremixed solution of 6 N HCl (0.34 mL) and THF (3.66 mL). The resultingreaction solution was stirred at rt for 40 min, and diluted with EtOAc(40 mL). The resulting mixture was washed with sat. NaHCO₃ (10 mL), andthen brine (10 mL). The organic phase was then dried over Na₂ SO₄. Thedried solution was filtered and concentrated to give the desired productS24-7 as a yellow foamy solid (204.2 mg). ¹H NMR (400 MHz, CDCl₃) δ15.55 (s, 1H), 10.33 (s, 1H), 7.50-7.47 (m, 3H), 7.38-7.31 (m, 3H),5.36, 5.32 (ABq, J=12.2 Hz, 2H), 3.94 (d, J=11.0 Hz, 1H), 3.86 (s, 3H),3.33 (dd, J=4.9, 15.9 Hz, 1H), 3.07-2.99 (m, 1H), 2.59-2.44 (m, 9H),2.16 (d, J=14.6 Hz, 1H), 1.51 (s, 9H), 0.82 (s, 9H), 0.25 (s, 3H), 0.11(s, 3H); MS (ESI) m/z 775.44 (M+H).

Hexamethyleneimine (8.5 μL, 0.072 mmol, 3.0 equiv), acetic acid (4 μL,0.072 mmol, 3.0 equiv) and sodium triacetoxyborohydride (10 mg, 0.048mmol, 2.0 equiv) were added sequentially to a solution of compound S24-7(one tenth of the above crude product, 0.024 mmol, 1.0 equiv) in1,2-dichloroethane (1 mL) at 23° C. After stirring for 2 h, the reactionmixture was quenched by the addition of saturated aqueous sodiumbicarbonate and brine (1:1, 20 mL) and extracted with dichloromethane(2×20 mL). The combined organic extracts were dried over anhydroussodium sulfate, filtered, and concentrated. The crude reductiveamination product was used directly for the deprotection steps.

Aqueous HF (48-50%, 0.3 mL) was added to a solution of the compound inTHF (0.6 mL) in a polypropylene reaction vessel at 23° C. The mixturewas stirred vigorously at 23° C. overnight and poured into aqueousK₂HPO₄ (3.6 g dissolved in 30 mL water). The mixture was extracted withEtOAc (50 mL). The organic phase was dried over anhydrous sodiumsulfate, filtered, and concentrated. The residue was used directly inthe next step without further purification.

Pd—C (10 wt %, 6.7 mg) was added in one portion into the yellow solutionof the above crude product in a mixture of HCl/MeOH (0.5 N, 96 μL, 2.0equiv) and MeOH (1 mL) at 23° C. The reaction vessel was sealed andpurged with hydrogen by briefly evacuating the flask followed byflushing with hydrogen gas (1 atm). The resulting mixture was stirred at23° C. for 30 min. The reaction mixture was then filtered through asmall Celite pad. The filtrate was concentrated. The residue waspurified by preparative reverse phase HPLC on a Waters Autopurificationsystem using a Phenomenex Polymerx 10μ RP-γ 100A column [10 μm,150×21.20 mm; flow rate, 20 mL/min; Solvent A: 0.05 N HCl/water; SolventB: CH₃CN; injection volume: 3.0 mL (0.05 N HCl/water); gradient: 5→60% Bover 10 min; mass-directed fraction collection]. Fractions containingthe desired product, eluting at 7.1-8.4 min, were collected andfreeze-dried to yield compound S24-9-1 (10.89 mg, 72% for 3 steps). ¹HNMR (400 MHz, CD₃OD, hydrochloride) δ 7.07 (s, 1H), 4.43 (d, J=12.8 Hz,1H), 4.29 (d, J=13.3 Hz, 1H), 4.12 (s, 1H), 3.73 (s, 3H), 3.47-3.41 (m,2H), 3.26-3.20 (m, 3H), 3.05-2.97 (m, 8H), 2.38 (t, J=14.6 Hz, 1H),2.28-2.25 (m, 1H), 2.00-1.82 (m, 4H), 1.73 (s, 4H), 1.70-1.60 (m, 1H);MS (ESI) m/z 556.33 (M+H).

Sodium triacetoxyborohydride (60 mg, 0.284 mmol, 2.0 equiv) was added toa solution of compound S24-7 (110 mg, 0.142 mmol, 1.0 equiv) in1,2-dichloroethane (1 mL) at 23° C. After stirring overnight, moresodium triacetoxyborohydride (60 mg, 0.284 mmol, 2.0 equiv) was added.The resulting reaction mixture was stirred at rt overnight, quenched bythe addition of saturated aqueous sodium bicarbonate and brine (1:1, 40mL) and extracted with dichloromethane (3×20 mL). The combined organicextracts were dried over anhydrous sodium sulfate, filtered, andconcentrated. The residue was purified by flash-column chromatography(8-66% ethyl acetate-hexanes) to afford the desired product S24-8 (70.2mg, 64%). ¹H NMR (400 MHz, CDCl₃) δ 15.69 (s, 1H), 7.48-7.47 (m, 2H),7.38-7.29 (m, 3H), 7.16 (s, 1H), 5.34 (s, 2H), 4.79, 4.69 (dABq, J=4.9,14.0 Hz, 2H), 3.97 (d, J=10.4 Hz, 1H), 3.71 (s, 3H), 3.27 (dd, J=4.9,15.3 Hz, 1H), 3.01-2.94 (m, 1H), 2.55-2.42 (m, 9H), 2.15-2.11 (m, 2H),1.53 (s, 9H), 0.82 (s, 9H), 0.25 (s, 3H), 0.11 (s, 3H); MS (ESI) m/z777.50 (M+H).

Compound S24-10 was prepared from compound S24-8 by following thegeneral HF deprotection procedure and Pd/C hydrogenation procedure: ¹HNMR (400 MHz, CD₃OD, hydrochloride) δ 6.92 (s, 1H), 4.66 (s, 2H), 4.08(s, 1H), 3.64 (s, 3H), 3.33 (s, 1H), 3.18 (dd, J=4.6, 15.6 Hz, 1H),3.03-2.92 (m, 8H), 2.28 (t, J=14.6 Hz, 1H), 2.24-2.19 (m, 1H), 1.67-1.57(m, 1H); MS (ESI) m/z 475.24 (M+H).

Ms₂O (13 mg, 0.075 mmol, 2.0 equiv) was added to a solution of alcoholS24-8 (29 mg, 0.037 mmol, 1.0 equiv) in THF (0.5 mL). Then TEA (10.4 μL,0.075 mmol, 2.0 equiv) was added. To another reaction flask charged witha suspension of 7-azabicyclo[2,2,1]heptane-HCl (15 mg, 0.112 mmol, 3.0equiv) in THF (0.5 mL) was added TEA (16 μL, 0.112 mmol, 3.0 equiv) andaqueous NaOH solution (8 N, 18 μL). The reaction mixtures were stirredfor 30 min and mixed. The resulting reaction mixture was stirred at rtfor 3 overnights, and diluted with EtOAc (50 mL), washed with pH=7phosphate buffer solution. The organic phase was separated, dried overanhydrous sodium sulfate. The dried solution was filtered andconcentrated. The crude product was used directly for the deprotectionreactions. MS (ESI) m/z 856.69 (M+H).

Aqueous HF (48-50%, 0.3 mL) was added to a solution of the abovecompound in THF (0.6 mL) in a polypropylene reaction vessel at 23° C.The mixture was stirred vigorously at 23° C. overnight and poured intoaqueous K₂HPO₄ (3.6 g dissolved in 30 mL water). The mixture wasextracted with EtOAc (50 mL). The organic phase was dried over anhydroussodium sulfate, filtered, and concentrated. The residue was useddirectly in the next step without further purification.

Pd—C (10 wt %, 15 mg) was added in one portion into the yellow solutionof the above crude product in a mixture of HCl/MeOH (0.5 N, 148 μL, 2.0equiv) and MeOH (1 mL) at 23° C. The reaction vessel was sealed andpurged with hydrogen by briefly evacuating the flask followed byflushing with hydrogen gas (1 atm). The resulting mixture was stirred at23° C. for 40 min. The reaction mixture was then filtered through asmall Celite pad. The filtrate was concentrated. The residue waspurified by preparative reverse phase HPLC on a Waters Autopurificationsystem using a Phenomenex Polymerx 10μ RP-γ 100A column [10 μm,150×21.20 mm; flow rate, 20 mL/min; Solvent A: 0.05 N HCl/water; SolventB: CH₃CN; injection volume: 3.0 mL (0.05 N HCl/water); gradient: 20→100%B over 10 min; mass-directed fraction collection]. Fractions containingthe desired product, eluting at 7.05-7.88 min, were collected andconcentrated to yield compound S24-9-2 (2.66 mg, 11% for 3 steps). ¹HNMR (400 MHz, CD₃OD, hydrochloride) δ 7.05 (s, 1H), 4.31, 4.19 (ABq,J=12.8 Hz, 2H), 4.09-4.07 (m, 3H), 3.72 (s, 3H), 3.23-3.20 (m, 1H),3.04-2.96 (m, 8H), 2.39-2.23 (m, 4H), 2.03-2.01 (m, 2H), 1.89-1.78 (m,4H), 1.70-1.60 (m, 1H); MS (ESI) m/z 554.47 (M+H).

Neopentylamine (5.6 μL, 0.048 mmol, 2.0 equiv), acetic acid (2.7 μL,0.048 mmol, 2.0 equiv) and sodium triacetoxyborohydride (7.6 mg, 0.036mmol, 1.5 equiv) were added sequentially to a solution of compound S24-7(one tenth of the above crude product, 0.024 mmol, 1.0 equiv) in1,2-dichloroethane (1 mL) at 23° C. After stirring for 3 h, formaldehyde(11 μL, 0.14 mmol, 6.0 equiv), acetic acid (4.1 μL, 0.072 mmol, 3.0equiv), and sodium triacetoxyborohydride (20 mg, 0.096 mmol, 4.0 equiv)were added. The resulting reaction mixture was stirred at rt for 1 h,and quenched by the addition of saturated aqueous sodium bicarbonate andbrine (1:1, 20 mL) and extracted with dichloromethane (2×20 mL). Thecombined organic extracts were dried over anhydrous sodium sulfate,filtered, and concentrated. The crude product was used directly for thedeprotection steps (see procedure for S24-9-1) to give the desiredproduct S24-9-3 (10.97 mg, 72% for four steps). ¹H NMR (400 MHz, CD₃OD,hydrochloride, a mixture of isomers) δ 7.08 (s, 0.6H), 7.06 (s, 0.4H),4.59 (d, J=12.8 Hz, 0.6H), 4.43, 4.39 (ABq, J=12.8 Hz, 0.8H), 4.22 (d,J=12.8 Hz, 0.6H), 4.13 (s, 1H), 3.78 (s, 1.2H), 3.73 (s, 1.8H),3.26-2.95 (m, 14H), 2.46-2.35 (m, 1H), 2.30-2.26 (m, 1H), 1.71-1.61 (m,1H), 1.04 (s, 5.4H), 1.02 (s, 3.6H); MS (ESI) m/z 558.36 (M+H).

The following compounds were prepared similarly to S24-9-1, S24-9-2 orS24-9-3 by using the corresponding amines and aldehydes.

¹H NMR (400 MHz, CD₃OD, hydrochloride) δ 7.01 (s, 1H), 4.48 (d, J=12.8Hz, 1H), 4.31 (d, J=12.8 Hz, 1H), 4.12 (s, 1H), 3.76-3.66 (m, 5H), 3.22(dd, J=4.1, 15.6 Hz, 1H), 3.12-2.98 (m, 9H), 2.86-2.75 (m, 3H), 2.39 (t,J=14.2 Hz, 1H), 2.29-2.25 (m, 1H), 1.87-1.52 (m, 7H); MS (ESI) m/z568.34 (M+H).

¹H NMR (400 MHz, CD₃OD, hydrochloride) δ 7.01 (s, 1H), 4.38 (d, J=13.7Hz, 1H), 4.23 (d, J=13.7 Hz, 1H), 4.13 (s, 1H), 3.76 (s, 3H), 3.23 (dd,J=4.1, 15.6 Hz, 1H), 3.08-2.98 (m, 8H), 2.86 (s, 2H), 2.39 (t, J=14.2Hz, 1H), 2.30-2.25 (m, 1H), 1.71-1.61 (m, 1H), 1.04 (s, 9H); MS (ESI)m/z 544.34 (M+H).

¹H NMR (400 MHz, CD₃OD, hydrochloride) δ 7.05 (s, 1H), 4.37 (d, J=13.3Hz, 1H), 4.24 (d, J=12.8 Hz, 1H), 4.12 (s, 1H), 3.72 (s, 3H), 3.51-3.43(m, 2H), 3.22 (dd, J=4.6, 15.6 Hz, 1H), 3.10-2.98 (m, 10H), 2.40 (t,J=14.2 Hz, 1H), 2.28-2.25 (m, 1H), 1.90-1.87 (m, 2H), 1.71-1.61 (m, 2H),1.52-1.42 (m, 2H), 0.99 (d, J=6.4 Hz, 3H); MS (ESI) m/z 556.34 (M+H).

¹H NMR (400 MHz, CD₃OD, hydrochloride) δ 7.00 (s, 1H), 4.23 (d, J=12.8Hz, 1H), 4.12 (s, 1H), 4.09 (d, J=12.8 Hz, 1H), 3.75 (s, 3H), 3.24 (dd,J=4.6, 15.6 Hz, 1H), 3.06-2.98 (m, 8H), 2.39 (t, J=14.2 Hz, 1H),2.28-2.24 (m, 1H), 1.71-1.61 (m, 1H), 1.47 (s, 9H); MS (ESI) m/z 530.35(M+H).

¹H NMR (400 MHz, CD₃OD, hydrochloride, a mixture of isomers) δ 7.01,6.99 (s, 1H), 4.92 (d, J=12.8 Hz, 0.6H), 4.60 (d, J=13.3 Hz, 0.4H),4.13, 4.12 (s, 1H), 3.96 (d, J=12.8 Hz, 0.4H), 3.80 (d, J=12.8 Hz,0.6H), 3.77, 3.73 (s, 3H), 3.24 (dd, J=4.6, 15.6 Hz, 1H), 3.27-3.20 (m,1H), 3.06-2.98 (m, 8H), 2.69 (s, 3H), 2.47-2.40 (m, 1H), 2.28-2.26 (m,1H), 1.71-1.64 (m, 1H), 1.55 (s, 9H); MS (ESI) m/z 544.32 (M+H).

¹H NMR (400 MHz, CD₃OD, hydrochloride) δ 7.02 (s, 1H), 4.36, 4.30 (ABq,J=13.3 Hz, 1H), 4.10 (s, 1H), 3.77 (s, 3H), 3.24 (dd, J=3.7, 15.6 Hz,1H), 3.05-2.94 (m, 9H), 2.40 (t, J=14.6 Hz, 1H), 2.27-2.24 (m, 1H),1.71-1.61 (m, 1H), 1.34 (d, J=6.9 Hz, 3H), 1.00 (s, 9H); MS (ESI) m/z558.34 (M+H).

¹H NMR (400 MHz, CD₃OD, hydrochloride, a mixture of isomers) δ 7.02 (s,1H), 4.54 (d, J=12.4 Hz, 0.6H), 4.43 (d, J=12.8 Hz, 0.4H), 4.11, 4.10(s, 1H), 4.02 (d, J=12.8 Hz, 0.4H), 3.88 (d, J=12.4 Hz, 0.6H), 3.78 (s,1.2H), 3.74 (s, 1.8H), 3.44-3.39 (m, 2H), 3.26-3.18 (m, 1H), 3.05-2.97(m, 8H), 2.46-2.35 (m, 1H), 2.29-2.24 (m, 1H), 2.12-2.07 (m, 2H),2.02-1.97 (m, 2H), 1.71-1.58 (m, 4H), 1.44, 1.43 (s, 3H); MS (ESI) m/z556.36 (M+H).

¹H NMR (400 MHz, CD₃OD, hydrochloride) δ 7.02 (s, 1H), 4.50 (d, J=12.8Hz, 1H), 4.32 (d, J=13.3 Hz, 1H), 4.12 (s, 1H), 3.74 (s, 3H), 3.55-3.50(m, 2H), 3.25-3.20 (m, 3H), 3.05-2.97 (m, 8H), 2.39 (t, J=14.6 Hz, 1H),2.28-2.24 (m, 1H), 2.17-2.03 (m, 4H), 1.70-1.60 (m, 1H); MS (ESI) m/z528.30 (M+H).

¹H NMR (400 MHz, CD₃OD, hydrochloride) δ 7.03 (s, 1H), 4.64 (d, J=13.3Hz, 1H), 4.13 (s, 1H), 4.08 (d, J=12.8 Hz, 1H), 3.75 (s, 3H), 3.66-3.60(m, 1H), 3.43-3.37 (m, 1H), 3.27-3.21 (m, 2H), 3.06-2.98 (m, 8H),2.44-2.34 (m, 2H), 2.28-2.25 (m, 1H), 2.13-2.07 (m, 1H), 2.03-1.97 (m,1H), 1.81-1.61 (m, 2H), 1.49 (d, J=6.4 Hz, 3H); MS (ESI) m/z 542.36(M+H).

¹H NMR (400 MHz, CD₃OD, hydrochloride) δ 7.00 (s, 1H), 4.32 (d, J=13.7Hz, 1H), 4.18 (d, J=13.7 Hz, 1H), 4.12 (s, 1H), 3.74 (s, 3H), 3.23 (dd,J=4.6, 15.6 Hz, 1H), 3.08-2.97 (m, 8H), 2.91 (d, J=7.3 Hz, 2H), 2.38 (t,J=14.6 Hz, 1H), 2.29-2.24 (m, 1H), 2.11-2.04 (m, 1H), 1.71-1.61 (m, 1H),1.04 (dd, J=0.9, 6.9 Hz, 6H); MS (ESI) m/z 530.39 (M+H).

¹H NMR (400 MHz, CD₃OD, hydrochloride) δ 6.98 (s, 1H), 4.78 (dt, J=47.2,4.6 Hz, 2H), 4.38 (d, J=13.7 Hz, 1H), 4.25 (d, J=13.7 Hz, 1H), 4.12 (s,1H), 3.74 (s, 3H), 3.45 (dt, J=26.6, 4.6 Hz, 2H), 3.22 (dd, J=4.6, 15.6Hz, 1H), 3.07-2.97 (m, 8H), 2.38 (t, J=14.2 Hz, 1H), 2.28-2.24 (m, 1H),1.70-1.60 (m, 1H); MS (ESI) m/z 520.31 (M+H).

¹H NMR (400 MHz, CD₃OD, hydrochloride, a mixture of isomers) δ 7.01 (s,1H), 4.62 (d, J=12.8 Hz, 0.6H), 4.43 (d, J=13.3 Hz, 0.4H), 4.29 (d,J=12.8 Hz, 0.4H), 4.12 (s, 1H), 4.04 (d, J=12.8 Hz, 0.6H), 3.76, 3.74(s, 3H), 3.26-3.18 (m, 1H), 3.15-2.98 (m, 10H), 2.83 (s, 1.2H), 2.78 (s,1.8H), 2.46-2.35 (m, 1H), 2.29-2.19 (m, 2H), 1.71-1.60 (m, 1H),1.11-1.01 (m, 6H); MS (ESI) m/z 544.36 (M+H).

¹H NMR (400 MHz, CD₃OD, hydrochloride, a mixture of isomers) δ 7.03 (s,1H), 4.96-4.83 (m, 2H), 4.73 (d, J=13.3 Hz, 0.5H), 4.60 (d, J=13.3 Hz,0.5H), 4.50 (d, J=13.3 Hz, 0.5H), 4.38 (d, J=13.3 Hz, 0.5H), 4.12 (s,1H), 3.76 (s, 3H), 3.72-3.57 (m, 2H), 3.25-3.16 (m, 3H), 3.05-2.97 (m,8H), 2.40 (t, J=14.6 Hz, 1H), 2.28-2.25 (m, 1H), 1.70-1.60 (m, 1H),1.22-1.20 (m, 1H), 0.82-0.78 (m, 2H), 0.48-0.46 (m, 2H); MS (ESI) m/z574.36 (M+H).

¹H NMR (400 MHz, CD₃OD, hydrochloride, a mixture of isomers) δ 7.04,7.00 (s, 1H), 4.76 (d, J=13.3 Hz, 0.8H), 4.30 (s, 0.4H), 4.11 (s, 1H),3.98 (d, J=12.8 Hz, 0.8H), 3.76, 3.74 (s, 3H), 3.37-3.30 (m, 1H), 3.22(dd, J=4.1, 15.6 Hz, 1H), 3.05-2.91 (m, 10H), 2.41 (t, J=13.7 Hz, 1H),2.27-2.24 (m, 1H), 2.02-1.98 (m, 2H), 1.86-1.82 (m, 2H), 1.72-1.61 (m,6.4H), 1.46 (d, J=6.9 Hz, 0.6H); MS (ESI) m/z 556.41 (M+H).

¹H NMR (400 MHz, CD₃OD, hydrochloride) δ 7.00 (s, 1H), 4.21 (d, J=12.8Hz, 1H), 4.11 (s, 1H), 4.07 (d, J=12.8 Hz, 1H), 3.74 (s, 3H), 3.24 (dd,J=4.6, 15.6 Hz, 1H), 3.07-2.97 (m, 8H), 2.38 (t, J=14.6 Hz, 1H),2.28-2.24 (m, 1H), 1.81 (q, J=7.8 Hz, 2H), 1.70-1.61 (m, 1H), 1.41 (s,6H), 1.04 (t, J=7.3 Hz, 3H); MS (ESI) m/z 544.36 (M+H).

¹H NMR (400 MHz, CD₃OD, hydrochloride, a mixture of isomers) δ 7.01 (s,1H), 4.72 (d, J=12.8 Hz, 0.7H), 4.60 (d, J=12.8 Hz, 0.3H), 4.12, 4.11(s, 1H), 3.96 (d, J=12.8 Hz, 0.3H), 3.81 (d, J=12.8 Hz, 0.7H), 3.77,3.73 (s, 3H), 3.26-3.19 (m, 1 H), 3.05-2.98 (m, 8H), 2.68 (s, 3H),2.48-2.32 (m, 1H), 2.28-2.24 (m, 1H), 1.94 (q, J=7.3 Hz, 2H), 1.72-1.62(m, 1H), 1.50, 1.48 (s, 6H), 1.11-1.07 (m, 3H); MS (ESI) m/z 558.39(M+H).

¹H NMR (400 MHz, CD₃OD, hydrochloride) δ 7.02 (s, 1H), 4.34 (d, J=12.8Hz, 1H), 4.20 (d, J=12.8 Hz, 1H), 4.12 (s, 1H), 3.75 (s, 3H), 3.24 (dd,J=4.1, 15.6 Hz, 1H), 3.05-2.97 (m, 8H), 2.38 (t, J=14.6 Hz, 1H),2.29-2.24 (m, 1H), 1.70-1.61 (m, 1H), 1.32 (s, 3H), 1.31 (s, 3H),1.24-1.18 (m, 1H), 0.73-0.68 (m, 2H), 0.62-0.58 (m, 2H); MS (ESI) m/z556.39 (M+H).

¹H NMR (400 MHz, CD₃OD, hydrochloride, a mixture of isomers) δ 7.03 (s,1H), 4.92-4.85 (m, 0.6H), 4.76 (d, J=12.8 Hz, 0.4H), 4.13, 4.12 (s, 1H),4.04 (d, J=12.8 Hz, 0.4H), 3.88 (d, J=12.8 Hz, 0.6H), 3.77 (s, 1.2H),3.74 (s, 1.8H), 3.28-3.20 (m, 1H), 3.06-2.98 (m, 8H), 2.76 (s, 3H),2.48-2.33 (m, 1H), 2.29-2.26 (m, 1H), 1.72-1.62 (m, 1H), 1.42 (s, 3H),1.37 (s, 3H), 1.32-1.29 (m, 1H), 0.83-0.74 (m, 2H), 0.69-0.66 (m, 2H);MS (ESI) m/z 570.39 (M+H).

¹H NMR (400 MHz, CD₃OD, hydrochloride) δ 7.04 (s, 1H), 4.53 (d, J=13.7Hz, 1H), 4.32 (d, J=13.7 Hz, 1H), 4.13 (s, 1H), 3.75 (s, 3H), 3.73-3.69(m, 2H), 3.23 (dd, J=4.6, 16.0 Hz, 1H), 3.08-2.97 (m, 8H), 2.40 (t,J=14.6 Hz, 1H), 2.31-2.23 (m, 3H), 1.79-1.73 (m, 2H), 1.71-1.61 (m, 1H),1.38 (d, J=6.9 Hz, 3H), 1.32 (d, J=6.4 Hz, 3H); MS (ESI) m/z 556.43(M+H).

¹H NMR (400 MHz, CD₃OD, hydrochloride) δ 7.05 (s, 1H), 4.37, 4.24 (ABq,J=13.3 Hz, 2H), 4.12 (s, 1H), 3.72 (s, 3H), 3.45 (br t, J=13.7 Hz, 2H),3.22 (dd, J=4.1, 15.1 Hz, 1H), 3.07-2.97 (m, 10H), 2.39 (t, J=14.6 Hz,1H), 2.27-2.24 (m, 1H), 1.93-1.90 (m, 2H), 1.82-1.75 (m, 3H), 1.70-1.61(m, 1H), 1.56-1.50 (m, 1H); MS (ESI) m/z 542.41 (M+H).

¹H NMR (400 MHz, CD₃OD, hydrochloride) δ 7.06 (s, 1H), 4.42 (d, J=12.8Hz, 1H), 4.28 (d, J=12.8 Hz, 1H), 4.12 (s, 1H), 3.73 (s, 3H), 3.38-3.30(m, 2H), 3.25-3.17 (m, 3H), 3.05-2.98 (m, 8H), 2.39 (t, J=14.6 Hz, 1H),2.27-2.25 (m, 1H), 1.76-1.60 (m, 5H), 1.09 (s, 3H), 1.03 (s, 3H); MS(ESI) m/z 570.39 (M+H).

¹H NMR (400 MHz, CD₃OD, hydrochloride, a mixture of isomers) δ 7.01,6.99 (s, 1H), 4.66, 4.58 (ABq, J=15.1 Hz, 0.67H), 4.43, 4.31 (ABq,J=15.1 Hz, 1.33H), 4.12 (s, 1H), 3.74, 3.70 (s, 3H), 3.59-3.55 (m,1.33H), 3.46-3.40 (m, 0.67H), 3.24-3.20 (m, 1H), 3.04-2.97 (m, 8H), 2.39(t, J=14.2 Hz, 1H), 2.27-2.24 (m, 1H), 1.98-1.76 (m, 4H), 1.70-1.58 (m,3H), 1.50 (d, J=6.0 Hz, 1H), 1.46 (d, J=6.0 Hz, 1H), 1.32 (d, J=6.4 Hz,2H), 1.24 (d, J=6.4 Hz, 2H); MS (ESI) m/z 570.52 (M+H).

¹H NMR (400 MHz, CD₃OD, hydrochloride, a mixture of isomers) δ 7.07-7.01(m, 1H), 4.54-4.24 (m, 2H), 4.11 (s, 1H), 3.92-3.89 (m, 1H), 3.75 (s,3H), 3.77-3.67 (m, 1H), 3.26-3.21 (m, 1H), 3.07-2.97 (m, 8H), 2.44-2.37(m, 2H), 2.26-2.22 (m, 2H), 1.92-1.65 (m, 3H), 1.43-1.30 (m, 6H); MS(ESI) m/z 556.49 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.10 (s, 1H), 4.46 (d, J=13.2 Hz, 1H), 4.33(d, J=12.8 Hz, 1H), 4.13 (s, 1H), 4.04-4.01 (m, 2H), 3.84-3.74 (m, 2H),3.72 (s, 3H), 3.41 (t, J=13.2 Hz, 2H), 3.27-2.97 (m, 11H), 2.40 (dd,J=14.8, 14.4 Hz, 1H), 2.28 (ddd, J=13.6, 5.6, 2.8 Hz, 1H), 1.65 (ddd,J=13.2, 13.2, 13.2 Hz, 1H); MS (ESI) m/z 544.3 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 6.99 (s, 1H), 4.31 (d, J=13.6 Hz, 1H), 4.17(d, J=13.6 Hz, 1H), 4.14 (s, 1H), 3.74 (s, 3H), 3.26-2.98 (m, 11H), 2.37(dd, J=14.8, 14.4 Hz, 1H), 2.28 (ddd, J=13.2, 5.6, 2.8 Hz, 1H),1.76-1.63 (m, 3H), 1.47-1.38 (m, 2H), 0.98 (t, J=7.2 Hz, 3H); MS (ESI)m/z 530.0 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 6.99 (s, 1H), 4.55, 4.08 (d, J=12.8 Hz, 1Htotal), 4.31 (dd, J=12.8, 12.8 Hz, 1H), 4.11 (s, 1H), 3.72 (s, 3H),3.28-2.96 (m, 11H), 2.79, 2.76 (s, 3H total), 2.39-2.23 (m, 2H),1.80-1.60 (m, 3H), 1.44-1.30 (m, 2H), 0.99-0.91 (m, 3H); MS (ESI) m/z544.1 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 6.94 (s, 1H), 4.52 (d, J=13.2 Hz, 1H), 4.34(d, J=13.2 Hz, 1H), 4.25-4.13 (m, 5H), 3.74 (s, 3H), 3.24-2.98 (m, 9H),2.61-2.58 (m, 1H), 2.44-2.25 (m, 3H), 1.65 (ddd, J=13.6, 13.6, 13.6 Hz,1H), MS (ESI) m/z 514.0 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.06 (s, 1H), 4.72, 4.60 (d, J=12.8 Hz, 1Htotal), 3.98, 3.82 (d, J=12.8 Hz, 1H total), 4.14-4.13 (m, 1H), 3.74,3.73 (s, 3H total), 3.28-2.99 (m, 9H), 2.69 (s, 3H), 2.41 (dd, J=14.8,14.8 Hz, 1H), 2.29 (ddd, J=11.2, 4.8, 2.4 Hz, 1H), 1.97-1.92 (m, 2H),1.72-1.60 (m, 1H), 1.48 (d, J=7.2 Hz, 6H), 1.09 (t, J=7.2 Hz, 3H); MS(ESI) m/z 558.1 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.06 (s, 1H), 4.38 (d, J=12.8 Hz, 1H), 4.25(d, J=13.2 Hz, 1H), 4.13 (s, 1H), 3.72 (s, 3H), 3.55-5.43 (m, 2H), 3.31(s, 3H), 3.27-2.98 (m, 13H), 2.39 (dd, J=14.4, 14.4 Hz, 1H), 2.27 (ddd,J=13.6, 5.6, 2.8 Hz, 1H), 1.97-1.90 (m, 3H), 1.71-1.50 (m, 3H); MS (ESI)m/z 586.1 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.07, 6.99 (s, 1H total), 4.34-4.31 (m, 1H),4.21-4.17 (m, 1H), 4.12 (s, 1H), 3.77, 3.73 (s, 3H total), 3.26-2.98 (m,11H), 2.38 (dd, J=15.2, 14.0 Hz, 1H), 2.29-2.10 (m, 2H), 1.96-1.90 (m,2H), 1.73-1.66 (m, 5H), 1.32-1.22 (m, 2H); MS (ESI) m/z 556.3 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.09, 7.01 (s, 1H total), 4.66-4.63 (m, 1H),4.43-4.33 (m, 1H), 4.13-4.06 (m, 1H), 3.79-3.73 (m, 3H), 3.27-2.98 (m,14H), 2.84-2.14 (m, 3H), 1.98-1.94 (m, 2H), 1.74-1.65 (m, 5H), 1.33-1.12(m, 2H); MS (ESI) m/z 570.1 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.02 (s, 1H), 4.52, 4.32 (d, J=13.2 Hz, 1Htotal), 4.45, 4.22 (d, J=13.2 Hz, 1H total), 4.12 (s, 1H), 3.76, 3.75(s, 3H total), 3.25-2.98 (m, 13H), 2.42-2.25 (m, 3H), 1.95-1.91 (m, 2H),1.72-1.62 (m, 5H), 1.41-1.35 (m, 3H), 1.29-1.19 (m, 2H); MS (ESI) m/z584.1 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.06, 7.04 (s, 1H total), 4.39 (dd, J=13.2,5.2 Hz, 1H), 4.27 (d, J=13.2 Hz, 1H), 4.12 (s, 1H), 4.05 (s, 1H), 3.72(s, 3H), 3.54-3.47 (m, 1H), 3.34-3.31 (m, 2H), 3.24-2.98 (m, 10H), 2.40(dd, J=14.4, 14.4 Hz, 1H), 2.25 (ddd, J=14.4, 5.2, 2.8 Hz, 1H),2.14-2.10 (m, 1H), 1.98-1.88 (m, 2H), 1.71-1.61 (m, 2H); MS (ESI) m/z558.2 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 6.98 (s, 1H), 4.41 (d, J=13.6 Hz, 1H), 4.27(d, J=13.2 Hz, 1H), 4.13 (s, 1H), 3.75 (s, 3H), 3.24-2.97 (m, 9H),2.81-2.79 (m, 1H), 2.37 (dd, J=14.4, 14.4 Hz, 1H), 2.27 (ddd, J=12.8,5.2, 2.8 Hz, 1H), 1.65 (ddd, J=12.8, 12.8, 12.8 Hz, 1H), 0.91 (d, J=5.2Hz, 4H); MS (ESI) m/z 514.3 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.04 (s, 1H), 4.64-4.53 (m, 1H), 4.72-4.34 (m,1H), 4.13 (s, 1H), 3.76 (s, 3H), 3.25-2.94 (m, 13H), 2.40 (dd, J=14.0,14.0 Hz, 1H), 2.27 (ddd, J=13.2, 5.2, 2.8 Hz, 1H), 1.66 (ddd, J=11.2,11.2, 11.2 Hz, 1H), 1.02-0.80 (m, 4H); MS (ESI) m/z 528.1 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.05, 7.03 (s, 1H total), 4.61, 4.42 (d,J=12.8 Hz, 1H total), 4.51, 4.35 (d, J=13.2 Hz, 1H total), 4.12 (s, 1H),3.75 (s, 3H), 3.39-3.33 (m, 2H), 3.25-2.90 (m, 9H), 2.89-2.85 (m, 1H),2.40 (dd, J=14.8, 14.4 Hz, 1H), 2.26 (ddd, J=13.6, 4.8, 2.8 Hz, 1H),1.67 (ddd, J=11.2, 11.2, 11.2 Hz, 1H), 1.46 (t, J=7.2 Hz, 3H), 1.04-0.67(m, 4H); MS (ESI) m/z 542.1 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.06, 7.05 (s, 1H total), 4.59-4.52 (m, 1H),4.50-4.40 (m, 2H), 4.15 (s, 1H), 3.81-3.74 (m, 4H), 3.59-3.48 (m, 2H),3.24-2.98 (m, 10H), 2.60-2.50 (m, 1H), 2.38 (dd, J=13.2, 12.8 Hz, 1H),2.28 (ddd, J=12.4, 5.2, 2.8 Hz, 1H), 2.14-2.07 (m, 1H), 1.98, 1.95 (s,3H total), 1.70-1.61 (m, 1H); MS (ESI) m/z 585.1 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 6.99 (s, 1H), 4.31 (d, J=13.6 Hz, 1H), 4.18(d, J=13.6 Hz, 1H), 4.13 (s, 1H), 3.74 (s, 3H), 3.26-2.98 (m, 11H), 2.38(dd, J=14.8, 14.4 Hz, 1H), 2.27 (ddd, J=13.2, 5.2, 2.8 Hz, 1H),1.72-1.60 (m, 4H), 0.97 (d, J=6.4 Hz, 6H); MS (ESI) m/z 544.0 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.02, 7.01 (s, 1H total), 4.58, 4.09 (d,J=12.8 Hz, 1H total), 4.36 (dd, J=12.8 Hz, 1H), 4.13 (s, 1H), 3.75 (s,3H), 3.25-2.98 (m, 11H), 2.81, 2.79 (s, 3H total), 2.40 (dd, J=14.0,13.6 Hz, 1H), 2.28 (ddd, J=12.4, 5.2, 2.8 Hz, 1H), 1.71-1.61 (m, 4H),0.96 (d, J=6.0 Hz, 6H); MS (ESI) m/z 558.1 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.03 (s, 1H), 4.46 (d, J=13.2 Hz, 1H), 4.26(d, J=12.4 Hz, 1H), 4.13 (s, 1H), 3.75 (s, 3H), 3.26-2.98 (m, 13H),2.44-2.36 (m, 1H), 2.30-2.26 (m, 1H), 1.71-1.60 (m, 4H), 1.37 (dd,J=7.2, 7.2 Hz, 3H), 0.97-0.95 (m, 6H); MS (ESI) m/z 572.1 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 6.96 (s, 1H), 4.35 (d, J=13.6 Hz, 1H), 4.21(d, J=14.0 Hz, 1H), 4.12 (s, 1H), 3.74 (s, 3H), 3.72-3.65 (m, 3H),3.25-2.97 (m, 11H), 2.37 (dd, J=14.8, 14.4 Hz, 1H), 2.26 (ddd, J=13.6,5.2, 2.8 Hz, 1H), 1.64 (ddd, J=13.2, 13.2, 13.2 Hz, 1H), 1.19 (d, J=6.0Hz, 6H); MS (ESI) m/z 560.2 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.00 (s, 1H), 4.65, 4.37 (d, J=13.2, Hz, 1Htotal), 4.47, 4.19 (d, J=13.2 Hz, 1H total), 4.12 (s, 1H), 3.82-3.79 (m,2H), 3.75, 3.74 (s, 3H total), 3.71-3.67 (m, 1H), 3.42-3.33 (m, 2H),3.24-2.97 (m, 9H), 2.87, 2.83 (s, 3H total), 2.39 (dd, J=14.8, 14.4 Hz,1H), 2.27 (ddd, J=12.0, 5.2, 2.8 Hz, 1H), 1.65 (ddd, J=13.2, 13.2, 13.2Hz, 1H), 1.12 (d, J=6.0 Hz, 6H); MS (ESI) m/z 574.1

¹H NMR (400 MHz, CD₃OD) δ 7.03 (s, 1H), 4.59, 4.40 (d, J=13.6 Hz, 1Htotal), 4.52, 4.33 (d, J=13.6 Hz, 1H total), 4.13 (s, 1H), 3.78-3.76 (m,5H), 3.71-3.66 (m, 1H), 3.45-3.34 (m, 2H), 3.25-2.98 (m, 11H), 2.40 (dd,J=13.6, 13.6 Hz, 1H), 2.27 (ddd, J=12.0, 5.2, 2.8 Hz, 1H), 1.66 (ddd,J=13.2, 13.2, 13.2 Hz, 1H), 1.42-1.34 (m, 3H), 1.21-1.19 (m, 6H); MS(ESI) m/z 588.1 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 6.99 (s, 1H), 4.31 (d, J=13.6 Hz, 1H), 4.17(d, J=13.6, Hz, 1H), 4.13 (s, 1H), 3.74 (s, 3H), 3.25-2.90 (m, 11H),2.38 (dd, J=14.4, 14.4 Hz, 1H), 2.29-2.26 (m, 1H), 1.83-1.64 (m, 7H),1.37-1.20 (m, 3H), 1.06-0.95 (m, 2H); MS (ESI) m/z 570.3 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.09-7.00 (m, 1H), 4.63, 4.30 (d, J=12.8 Hz,1H total), 4.43, 4.04 (d, J=13.2 Hz, 1H total), 4.14 (s, 1H), 3.81-3.74(m, 3H), 3.25-2.79 (m, 14H), 2.40 (dd, J=15.6, 14.8 Hz, 1H), 2.30-2.27(m, 1H), 1.95-1.64 (m, 7H), 1.36-1.28 (m, 3H), 1.06-0.95 (m, 2H); MS(ESI) m/z 584.1 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.01 (s, 1H), 4.50, 4.30 (d, J=13.2 Hz, 1Htotal), 4.43, 4.19 (d, J=13.6 Hz, 1H total), 4.11 (s, 1H), 3.76, 3.75(s, 3H total), 3.25-2.98 (m, 13H), 2.45-2.36 (m, 1H), 2.28-2.25 (m, 1H),1.92-1.62 (m, 7H), 1.41-1.14 (m, 6H), 1.06-0.95 (m, 2H); MS (ESI) m/z598.1 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.01 (s, 1H), 4.50, 4.08 (d, J=12.8 Hz, 1Htotal), 4.34, 4.30 (d, J=13.6 Hz, 1H total), 4.14 (s, 1H), 3.80, 3.75(s, 3H total), 3.27-2.74 (m, 15H), 2.44-2.12 (m, 4H), 2.05-1.80 (m, 4H),1.65 (ddd, J=13.2, 13.2, 13.2 Hz, 1H); MS (ESI) m/z 556.1 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.00 (s, 1H), 4.40 (t, J=13.2 Hz, 1H), 4.20(d, J=12.8 Hz, 1H), 4.13 (s, 1H), 3.75 (s, 3H), 3.23-2.83 (m, 14H), 2.40(dd, J=14.8, 13.6 Hz, 1H), 2.28 (ddd, J=12.4, 5.2, 2.8 Hz, 1H),2.20-2.14 (m, 2H), 2.04-1.97 (m, 1H), 1.92-1.84 (m, 3H), 1.66 (ddd,J=13.2, 13.2, 13.2 Hz, 1H), 1.39-1.30 (m, 3H); MS (ESI) m/z 570.1 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.00 (s, 1H), 6.34 (t, J=53.6 Hz, 1H), 4.43(d, J=13.6 Hz, 1H), 4.30 (d, J=13.2 Hz, 1H), 4.12 (s, 1H), 3.75 (s, 3H),3.63 (ddd, J=13.6, 13.6, 13.6, 2H), 3.25-2.98 (m, 9H), 2.39 (dd, J=14.4,14.8 Hz, 1H), 2.27 (ddd, J=12.4, 5.2, 2.8 Hz, 1H), 1.65 (ddd, J=13.2,13.2, 13.2 Hz, 1H); MS (ESI) m/z 538.1 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.04 (s, 1H), 6.46 (t, J=53.6 Hz, 1H), 4.60(d, J=13.2 Hz, 1H), 4.41 (d, J=13.2 Hz, 1H), 4.12 (s, 1H), 3.78-3.72 (m,5H), 3.36-3.34 (m, 2H), 3.25-2.98 (m, 9H), 2.41 (dd, J=14.4, 14.4 Hz,1H), 2.27 (ddd, J=12.0, 5.2, 2.8 Hz, 1H), 1.66 (ddd, J=12.4, 12.4, 12.4Hz, 1H), 1.41 (t, J=7.2 Hz, 3H); MS (ESI) m/z 565.9 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.00 (s, 1H), 4.45 (d, J=13.2 Hz, 1H), 4.33(d, J=13.2 Hz, 1H), 4.11 (s, 1H), 4.06 (t, J=8.8 Hz, 2H), 3.75 (s, 3H),3.26-2.97 (m, 9H), 2.39 (dd, J=14.4, 14.4 Hz, 1H), 2.26 (ddd, J=13.2,5.2, 2.8 Hz, 1H), 1.66 (ddd, J=14.0, 14.0, 14.0 Hz, 1H); MS (ESI) m/z556.0 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.03 (s, 1H), 4.52 (d, J=13.2 Hz, 1H), 4.35(d, J=12.8 Hz, 1H), 4.20-4.12 (m, 3H), 3.74 (s, 3H), 3.26-2.92 (m, 12H),2.40 (dd, J=14.8, 14.8 Hz, 1H), 2.27 (ddd, J=15.2, 5.2, 2.8 Hz, 1H),1.66 (ddd, J=13.2, 13.2, 13.2 Hz, 1H); MS (ESI) m/z 570.0 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.04 (s, 1H), 4.59 (d, J=13.6 Hz, 1H), 4.43(d, J=13.6 Hz, 1H), 4.21-4.12 (m, 3H), 3.74 (s, 3H), 3.26-2.98 (m, 11H),2.40 (dd, J=14.8, 14.4 Hz, 1H), 2.27 (ddd, J=13.2, 5.2, 2.8 Hz, 1H),1.66 (ddd, J=13.2, 13.2, 13.2 Hz, 1H); 1.18-1.15 (m, 1H), 0.78 (d, J=7.6Hz, 2H), 0.42 (d, J=4.4 Hz, 2H); MS (ESI) m/z 610.0 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.01 (s, 1H), 4.43 (dd, J=13.2, 13.2 Hz, 1H),4.23 (dd, J=12.8, 12.8 Hz, 1H), 4.11 (s, 1H), 3.73 (s, 3H), 3.28-2.96(m, 13H), 2.38-2.24 (m, 2H), 1.76-1.60 (m, 3H), 1.41-1.31 (m, 5H),0.99-0.91 (m, 3H); MS (ESI) m/z 558.1 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.05 (s, 1H), 6.49 (t, J=53.2 Hz, 1H), 4.70(d, J=13.2 Hz, 1H), 4.51 (d, J=13.6 Hz, 1H), 4.13 (s, 1H), 3.85-3.76 (m,5H), 3.25-2.98 (m, 11H), 2.41 (dd, J=14.8, 14.4 Hz, 1H), 2.27 (ddd,J=13.2, 5.2, 2.8 Hz, 1H), 1.66 (ddd, J=13.6, 13.6, 13.6 Hz, 1H),1.29-1.24 (m, 1H), 0.82 (d, J=7.6 Hz, 2H), 0.48 (d, J=4.8 Hz, 2H); MS(ESI) m/z 592.0 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 6.97 (s, 1H), 4.28 (d, J=13.6 Hz, 1H),4.16-4.12 (m, 2H), 3.74 (s, 3H), 3.25-2.98 (m, 11H), 2.77-2.69 (m, 1H),2.37 (dd, J=14.8, 14.4 Hz, 1H), 2.27 (ddd, J=13.6, 5.2, 2.8 Hz, 1H),2.20-2.16 (m, 2H), 2.03-1.80 (m, 4H), 1.65 (ddd, J=14.0, 14.0, 14.0 Hz,1H); MS (ESI) m/z 542.1 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.01 (s, 1H), 4.63, 4.22 (d, J=13.2 Hz, 1Htotal), 4.40 (dd, J=13.6 Hz, 1H), 4.13 (s, 1H), 3.76 (s, 3H), 3.25-2.98(m, 13H), 2.88-2.82 (m, 1H), 2.40 (dd, J=14.4, 14.4 Hz, 1H), 2.29-2.14(m, 3H), 2.03-1.80 (m, 4H), 1.65 (ddd, J=14.0, 14.0, 14.0 Hz, 1H),1.22-1.12 (m, 1H), 0.83-0.76 (m, 2H), 0.48-0.40 (m, 2H); MS (ESI) m/z596.1 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.00 (s, 1H), 4.62, 4.28 (d, J=13.2 Hz, 1Htotal), 4.43, 4.03 (d, J=13.2 Hz, 1H total), 4.12 (s, 1H), 3.77, 3.74(s, 3H total), 3.26-2.98 (m, 11H), 2.83, 2.79 (s, 3H total), 2.40 (dd,J=14.8, 14.8 Hz, 1H), 2.27 (ddd, J=13.6, 5.2, 2.8 Hz, 1H), 1.99-1.92 (m,1H), 1.80-1.62 (m, 5H), 1.42-1.20 (m, 3H), 1.10-0.90 (m, 2H); MS (ESI)m/z 584.1 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 6.94 (s, 1H), 4.31 (d, J=13.6 Hz, 1H), 4.15(d, J=14.4 Hz, 1H), 4.11 (s, 1H), 3.74 (s, 3H), 3.25-2.97 (m, 9H), 2.74(s, 3H), 2.38 (dd, J=14.4, 14.8 Hz, 1H), 2.26 (ddd, J=13.6, 5.2, 2.8 Hz,1H), 1.66 (ddd, J=13.6, 13.6, 13.6 Hz, 1H), MS (ESI) m/z 488.0 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.53-7.47 (m, 5H), 6.93 (s, 1H), 4.32-4.25 (m,3H), 4.14 (d, J=13.2 Hz, 1H), 4.11 (s, 1H), 3.59 (s, 3H), 3.22-2.97 (m,9H), 2.36 (dd, J=14.8, 14.4 Hz, 1H), 2.25 (ddd, J=14.0, 5.2, 2.8 Hz,1H), 1.64 (ddd, J=13.2, 13.2, 13.2 Hz, 1H); MS (ESI) m/z 564.1 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.53-7.49 (m, 5H), 6.88 (s, 1H), 4.51-4.48 (m,1H), 4.15-4.11 (m, 2H), 3.91 (d, J=13.2 Hz, 1H), 3.47 (s, 3H), 3.17-2.97(m, 9H), 2.36-2.23 (m, 2H), 1.73 (d, J=6.8 Hz, 3H), 1.68-1.58 (m, 1H);MS (ESI) m/z 578.1 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.54-7.48 (m, 5H), 6.90 (s, 1H), 4.49-4.46 (m,1H), 4.11 (s, 1H), 3.98 (dd, J=13.2, 12.8 Hz, 2H), 3.39 (s, 3H),3.21-2.97 (m, 9H), 2.36-2.23 (m, 2H), 1.71 (d, J=6.4 Hz, 3H), 1.68-1.59(m, 1H); MS (ESI) m/z 578.1 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.01 (s, 1H), 4.55, 4.10 (d, J=13.2 Hz, 1Htotal), 4.35 (dd, J=13.2, 13.2 Hz, 1H), 4.12 (s, 1H), 3.75 (s, 3H),3.34-2.98 (m, 11H), 2.81, 2.78 (s, 3H total), 2.45-2.35 (m, 1H),2.29-2.25 (m, 1H), 1.66 (ddd, J=12.8, 12.8, 12.8 Hz, 1H), 1.43-1.35 (m,3H); MS (ESI) m/z 516.1 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.60-7.53 (m, 5H), 6.98, 6.95 (s, 1H total),4.53, 4.03 (d, J=12.8 Hz, 1H), 4.42-4.25 (m, 3H), 4.13 (s, 1H), 3.52,3.32 (s, 3H total), 3.18-2.97 (m, 9H), 2.83, 2.81 (s, 3H total),2.37-2.24 (m, 2H), 1.63 (ddd, J=12.4, 12.4, 12.4 Hz, 1H); MS (ESI) m/z578.1 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.57-7.49 (m, 5H), 6.95, 6.85 (s, 1H total),4.54-4.10 (m, 5H), 3.55, 3.34 (s, 3H total), 3.26-2.97 (m, 11H),2.38-2.22 (m, 2H), 1.64 (ddd, J=13.2, 13.2, 13.2 Hz, 1H), 1.46-1.41 (m,3H); MS (ESI) m/z 592.1 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.59-7.48 (m, 5H), 6.97, 6.86 (s, 1H total),4.68, 4.28 (d, J=12.8 Hz, 1H total), 4.59 (dd, J=12.8, 12.8 Hz, 1H),4.42-4.33 (m, 2H), 4.13, 4.12 (s, 1H total), 3.57, 3.35 (s, 3H total),3.17-2.98 (m, 11H), 2.37-2.25 (m, 2H), 1.64 (ddd, J=12.8, 12.8, 12.8 Hz,1H), 1.29-1.26 (m, 1H), 0.82-0.80 (m, 2H), 0.44-0.42 (m, 2H); MS (ESI)m/z 618.1 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.00 (s, 1H), 4.54 (d, J=13.2 Hz, 1H), 4.36(d, J=12.8 Hz, 1H), 4.12 (s, 1H), 3.78 (s, 3H), 3.26-2.98 (m, 9H), 2.39(dd, J=14.4, 14.4 Hz, 1H), 2.28-2.25 (m, 1H), 1.71-1.57 (m, 2H),1.03-1.01 (m, 2H), 0.81-0.79 (m, 2H), 0.75-0.71 (m, 2H), 0.43-0.40 (m,2H); MS (ESI) m/z 554.0 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.06 (s, 1H), 4.70, 4.46 (d, J=12.8 Hz, 1Htotal), 4.61 (s, 1H), 4.13, 4.12 (s, 1H total), 3.80, 3.76 (s, 3Htotal), 3.25-2.94 (m, 12H), 2.46-2.25 (m, 2H), 1.70-1.61 (m, 2H),1.14-1.10 (m, 2H), 0.96-0.70 (m, 4H), 0.40-0.31 (m, 2H); MS (ESI) m/z568.2 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.07 (s, 1H), 4.67 (dd, J=14.4, 14.0 Hz, 1H),4.52 (dd, J=12.4, 12.4 Hz, 1H), 4.13 (s, 1H), 3.77, 3.75 (s, 3H total),3.69-3.61 (m, 1H), 3.48-3.43 (m, 1H), 3.26-2.98 (m, 9H), 2.40 (dd,J=13.6, 13.6 Hz, 1H), 2.29-2.25 (m, 1H), 1.71-1.61 (m, 2H), 1.39-1.36(m, 3H), 1.29-1.22 (m, 1H), 0.96-0.70 (m, 5H), 0.42-0.31 (m, 2H); MS(ESI) m/z 582.0 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.00 (s, 1H), 4.24 (d, J=12.8 Hz, 1H),4.14-4.10 (m, 2H), 3.76 (s, 3H), 3.27-2.98 (m, 9H), 2.39 (dd, J=14.8,14.4 Hz, 1H), 2.27 (ddd, J=13.6, 4.8, 2.8 Hz, 1H), 1.98-1.80 (m, 8H),1.66 (ddd, J=13.6, 13.6, 13.6 Hz, 1H), 1.50 (s, 3H); MS (ESI) m/z 556.0(M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.01 (s, 1H), 4.24 (d, J=12.8 Hz, 1H),4.13-4.18 (m, 2H), 3.75 (s, 3H), 3.27-2.97 (m, 9H), 2.39 (dd, J=14.8,14.8 Hz, 1H), 2.27 (ddd, J=13.6, 4.8, 2.4 Hz, 1H), 1.97-1.91 (m, 2H),1.80-1.53 (m, 8H), 1.50 (s, 3H), 1.32-1.25 (m, 1H); MS (ESI) m/z 570.0(M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.70-7.67 (m, 2H), 7.57-7.47 (m, 3H), 6.87 (s,1H), 4.13 (s, 1H), 3.81 (dd, J=12.8 Hz, 2H), 3.34 (s, 3H), 3.19-2.98 (m,9H), 2.35-2.23 (m, 2H), 1.88 (d, J=6.8 Hz, 6H), 1.63 (ddd, J=13.6, 13.6,13.6 Hz, 1H); MS (ESI) m/z 592.0 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 6.99 (s, 1H), 4.45 (d, J=12.8 Hz, 1H), 4.25(d, J=13.2 Hz, 1H), 4.11 (s, 1H), 3.75 (s, 3H), 3.25-2.98 (m, 9H), 2.90(s, 3H), 2.85 (s, 3H), 2.40 (dd, J=14.8, 14.4 Hz, 1H), 2.27-2.24 (m,1H), 1.66 (ddd, J=13.2, 13.2, 13.2 Hz, 1H); MS (ESI) m/z 502.0 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.02 (s, 1H), 4.43 (d, J=13.6 Hz, 1H), 4.29(d, J=13.6 Hz, 1H), 4.11 (s, 1H), 4.06-3.99 (m, 2H), 3.72 (s, 3H),3.26-2.97 (m, 11H), 2.39 (dd, J=14.8, 14.4 Hz, 1H), 2.26 (ddd, J=13.6,4.8, 2.8 Hz, 1H), 1.66 (ddd, J=13.6, 13.6, 13.6 Hz, 1H), 1.36 (t, J=7.2Hz, 3H); MS (ESI) m/z 584.1 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.00 (s, 1H), 4.29 (d, J=13.2 Hz, 1H), 4.15(d, J=13.6 Hz, 1H), 4.13 (s, 1H), 3.75 (s, 3H), 3.50-3.44 (m, 1H),3.26-2.98 (m, 9H), 2.38 (dd, J=14.8, 14.4 Hz, 1H), 2.29-2.25 (m, 1H),1.66 (ddd, J=13.6, 13.6, 13.6 Hz, 1H), 1.40 (d, J=6.4 Hz, 6H); MS (ESI)m/z 516.3 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.03 (s, 1H), 6.46 (t, J=53.2 Hz, 1H), 4.60(d, J=13.2 Hz, 1H), 4.39 (d, J=13.6 Hz, 1H), 4.11 (s, 1H), 3.82-3.74 (m,5H), 3.26-2.95 (m, 12H), 2.42 (dd, J=14.8, 14.8 Hz, 1H), 2.28-2.24 (m,1H), 1.67 (ddd, J=13.2, 13.2, 13.2 Hz, 1H); MS (ESI) m/z 552.1 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.00, 6.99 (s, 1H total), 4.41 (d, J=12.8 Hz,1H), 4.27 (d, J=13.2 Hz, 1H), 4.06 (s, 1H), 3.65 (s, 3H), 3.51-3.47 (m,1H), 3.28-3.25 (m, 2H), 3.17-3.12 (m, 1H), 2.98-2.90 (m, 9H), 2.30 (dd,J=14.4, 14.4 Hz, 1H), 2.21-2.17 (m, 1H), 1.93-1.88 (m, 1H), 1.80-1.73(m, 1H), 1.62-1.40 (m, 5H), 0.82-0.73 (m, 6H); MS (ESI) m/z 584.1 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 6.99 (s, 1H), 4.34-4.29 (m, 1H), 4.22-4.15 (m,1H), 4.03 (s, 1H), 3.64 (s, 3H), 3.51-3.41 (m, 2H), 3.27 (s, 3H),3.17-2.90 (m, 12H), 2.30 (dd, J=14.4, 14.4 Hz, 1H), 2.19-2.14 (m, 2H),2.03-1.99 (m, 1H), 1.92-1.80 (m, 1H), 1.61-1.52 (m, 2H); MS (ESI) m/z572.0 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 6.90 (s, 1H), 4.20 (dd, J=13.6, 5.2 Hz, 1H),4.09-4.02 (m, 2H), 3.66 (s, 3H), 3.16-2.88 (m, 10H), 2.29 (dd, J=14.4,14.4 Hz, 1H), 2.19-2.16 (m, 1H), 1.85-1.80 (m, 1H), 1.58-1.51 (m, 2H),1.29 (d, J=6.4 Hz, 3H), 0.94 (t, J=7.6 Hz, 3H); MS (ESI) m/z 530.0(M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.00 (s, 1H), 4.33 (d, J=13.2 Hz, 1H),4.19-4.14 (m, 2H), 3.74 (s, 3H), 3.24-2.98 (m, 11H), 2.45-2.38 (m, 3H),2.29-2.26 (m, 1H), 2.03-1.93 (m, 5H), 1.67-1.54 (m, 2H), 1.34-1.32 (m,1H), 1.24-1.20 (m, 3H), 1.02-0.97 (m, 3H); MS (ESI) m/z 610.4 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.30 (s, 4H), 6.98 (s, 1H), 4.67-4.62 (m, 5H),4.48 (d, J=13.2 Hz, 1H), 4.03 (s, 1H), 3.66 (s, 3H), 3.19-3.15 (m, 1H),2.97-2.80 (m, 8H), 2.32 (dd, J=14.4, 14.4 Hz, 1H), 2.17 (ddd, J=14.4,5.2, 2.8 Hz, 1H), 1.58 (ddd, J=13.2, 13.2, 13.2 Hz, 1H); MS (ESI) m/z576.1 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 6.94 (s, 1H), 4.53-4.47 (m, 1H), 4.40-4.32 (m,1H), 4.28-4.19 (m, 1H), 4.12 (s, 1H), 3.89-3.85 (m, 2H), 3.73 (s, 3H),3.24-2.98 (m, 11H), 2.38 (dd, J=14.8, 14.8 Hz, 1H), 2.27-2.24 (m, 1H),1.70-1.61 (m, 1H), 1.32, 1.25 (d, J=7.2, 7.2 Hz, 3H total); MS (ESI) m/z528.4 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.07 (s, 1H), 4.63 (d, J=13.2 Hz, 1H), 4.47(d, J=13.2 Hz, 1H), 4.14 (s, 1H), 3.96-3.91 (m, 2H), 3.80-3.72 (m, 5H),3.26-2.98 (m, 9H), 2.70-2.66 (m, 2H), 2.39 (dd, J=14.4, 14.4 Hz, 1H),2.30-2.26 (m, 1H), 1.66 (ddd, J=13.2, 13.2, 13.2 Hz, 1H); MS (ESI) m/z563.9 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 6.92 (s, 1H), 4.36 (d, J=13.2 Hz, 1H), 4.11(d, J=13.2 Hz, 1H), 4.03 (s, 1H), 3.68 (s, 3H), 3.18-2.90 (m, 9H), 2.63(dd, J=6.4, 6.4 Hz, 1H), 2.31 (dd, J=14.4, 14.4 Hz, 1H), 2.20-2.16 (m,1H), 1.58 (ddd, J=13.2, 13.2, 13.2 Hz, 1H), 1.39 (d, J=6.8 Hz, 3H),1.01-0.99 (m, 1H), 0.72-0.62 (m, 2H), 0.51-0.47 (m, 1H), 0.32-0.27 (m,1H); MS (ESI) m/z 542.1 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 6.95 (s, 1H), 4.59-4.50 (m, 1H), 4.04-3.98 (m,2H), 3.71, 3.67 (s, 3H total), 3.14-2.60 (m, 13H), 2.34-2.29 (m, 1H),2.19-2.16 (m, 1H), 1.60-1.52 (m, 1H), 1.48-1.42 (m, 3H), 1.14-1.08 (m,1H), 0.78-0.60 (m, 2H), 0.42-0.31 (m, 2H); MS (ESI) m/z 556.0 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 6.96, 6.95 (s, 1H total), 4.62-4.49 (m, 1H),4.24-4.14 (m, 1H), 4.02 (s, 1H), 3.73-3.67 (m, 3H), 3.18-2.81 (m, 12H),2.34-2.31 (m, 1H), 2.21-2.18 (m, 1H), 1.63-1.54 (m, 1H), 1.44-1.39 (m,3H), 1.26-1.12 (m, 4H), 0.80-0.60 (m, 2H), 0.48-0.30 (m, 2H); MS (ESI)m/z 570.0 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.30-7.22 (m, 4H), 7.07, 7.05 (s, 1H total),4.57-4.47 (m, 1H), 4.33-4.30 (m, 2H), 4.13 (s, 1H), 3.78-3.75 (m, 3H),3.59-3.52 (m, 1H), 3.50-3.40 (m, 3H), 3.26-2.98 (m, 9H), 2.79, 2.78 (s,3H total), 2.45-2.38 (m, 1H), 2.30-2.26 (m, 1H), 1.70-1.61 (m, 1H); MS(ESI) m/z 604.0 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.30-7.22 (m, 4H), 7.06, 7.04 (s, 1H total),4.47-4.24 (m, 3H), 4.13 (s, 1H), 3.75 (s, 3H), 3.57-3.41 (m, 4H),3.26-2.98 (m, 11H), 2.41-2.36 (m, 1H), 2.30-2.26 (m, 1H), 1.70-1.61 (m,1H), 1.40-1.36 (m, 3H); MS (ESI) m/z 618.0 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.09, 7.06 (s, 1H total), 4.56-4.49 (m, 1H),4.40-4.35 (m, 1H), 4.12 (s, 1H), 3.78, 3.75 (s, 3H total), 3.56-3.55 (m,1H), 3.43-3.34 (m, 2H), 3.24-2.89 (m, 10H), 2.56-2.54 (m, 1H), 2.42-2.36(m, 2H), 2.39-2.25 (m, 1H), 1.74-1.38 (m, 9H); MS (ESI) m/z 582.3 (M+H)

¹H NMR (400 MHz, CD₃OD) δ 7.38-7.20 (m, 5H), 7.10 (s, 1H), 4.45 (d,J=13.2 Hz, 1H), 4.32 (d, J=12.8 Hz, 1H), 4.12 (s, 1H), 3.75, 3.74 (s, 3Htotal), 3.65-3.58 (m, 2H), 3.29-3.22 (m, 3H), 3.05-2.89 (m, 9H),2.45-2.42 (m, 1H), 2.28-2.23 (m, 1H), 2.08-1.95 (m, 4H), 1.72-1.66 (m,1H); MS (ESI) m/z 618.1 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.01 (s, 1H), 4.64, 4.20 (d, J=12.4 Hz, 1Htotal), 4.45-4.43 (m, 1H), 4.11 (s, 1H), 3.74 (s, 3H), 3.23-2.88 (m,16H), 2.44-2.40 (m, 1H), 2.27-2.23 (m, 1H), 1.69-1.60 (m, 1H); MS (ESI)m/z 534.1 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.02 (s, 1H), 4.54 (d, J=12.8 Hz, 1H), 4.34(d, J=13.6 Hz, 1H), 4.10 (s, 1H), 3.74 (s, 3H), 3.61-3.54 (m, 2H),3.04-2.96 (m, 13H), 2.43-2.36 (m, 1H), 2.26-2.23 (m, 1H), 1.70-1.60 (m,1H), 1.41-1.35 (m, 3H); MS (ESI) m/z 548.1 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.02 (s, 1H), 4.32 (d, J=−13.2 Hz, 1H), 4.19(d, J=13.6 Hz, 1H), 4.13 (s, 1H), 3.76 (s, 3H), 3.25-2.98 (m, 10H),2.42-2.35 (m, 1H), 2.29-2.26 (m, 1H), 2.19-2.13 (m, 1H), 1.70-1.61 (m,1H), 1.31 (d, J=6.8 Hz, 3H), 1.04 (d, J=7.2 Hz, 3H), 0.94 (d, J=7.2 Hz,3H); MS (ESI) m/z 544.4 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.02 (s, 1H), 4.35 (d, J=13.2 Hz, 1H), 4.22(d, J=13.6 Hz, 1H), 4.15 (s, 1H), 3.77 (s, 3H), 3.28-3.01 (m, 11H), 2.41(dd, J=14.4, 14.8 Hz, 1H), 2.32-2.28 (m, 1H), 1.70-1.66 (m, 3H), 1.00(s, 9H); MS (ESI) m/z 558.1 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.03-6.69 (m, 1H), 4.58, 4.19 (d, J=13.6 Hz,1H total), 4.43-4.31 (m, 1H), 4.13 (s, 1H), 3.75, 3.74 (s, 3H total),3.26-2.98 (m, 11H), 2.81, 2.80 (s, 3H total), 2.45-2.39 (m, 1H),2.35-2.26 (m, 1H), 1.77-1.65 (m, 3H), 1.02-0.96 (m, 9H); MS (ESI) m/z572.2 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 6.94 (s, 1H), 4.37 (dd, J=13.2, 7.6 Hz, 1H),4.18 (dd, J=13.6, 4.0 Hz, 1H), 4.02 (s, 1H), 3.66 (s, 3H), 3.17-2.88 (m,13H), 2.36-2.27 (m, 1H), 2.18-2.15 (m, 1H), 1.62-1.53 (m, 3H), 1.28 (q,J=7.6 Hz, 3H), 0.86 (d, J=5.2 Hz, 9H); MS (ESI) m/z 586.4 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 6.89 (s, 1H), 4.21 (d, J=13.6 Hz, 1H), 4.07(d, J=13.6 Hz, 1H), 4.02 (s, 1H), 3.64 (s, 3H), 3.21-2.82 (m, 11H), 2.29(dd, J=14.4, 14.8 Hz, 1H), 2.20-2.15 (m, 1H), 1.90-1.80 (m, 1H),1.70-1.43 (m, 11H), 1.23-1.18 (m, 2H); MS (ESI) m/z 584.3 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.02 (d, J=6.4 Hz, 1H), 4.44, 4.33 (d, J=13.2Hz, 1H total), 4.21-4.06 (m, 2H), 4.08 (d, J=12.0 Hz, 3H), 3.32-2.82 (m,14H), 2.42 (dd, J=14.8, 14.8 Hz, 1H), 2.31-2.28 (m, 1H), 2.14-1.55 (m,12H), 1.32-1.20 (m, 2H); MS (ESI) m/z 598.0 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 6.93 (s, 1H), 4.39 (dd, J=13.6, 13.6 Hz, 1H),4.20, 4.12 (d, J=13.2 Hz, 1H total), 4.02 (s, 1H), 3.69, 3.67 (s, 3Htotal), 3.18-2.89 (m, 13H), 2.38-2.28 (m, 1H), 2.19-2.16 (m, 1H),1.90-1.50 (m, 12H), 1.46-1.38 (m, 3H), 1.34-1.20 (m, 2H); MS (ESI) m/z612.1 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.01 (s, 1H), 4.39-4.28 (m, 1H), 4.25-4.22 (m,1H), 4.13 (s, 1H), 3.78 (s, 3H), 3.29-3.00 (m, 11H), 2.46-2.39 (m, 1H),2.30-2.27 (m, 1H), 1.74-1.65 (m, 1H), 1.20-1.15 (m, 1H), 0.77 (d, J=6.8Hz, 2H), 0.46 (d, J=5.6 Hz, 2H); MS (ESI) m/z 528.1 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.05, 7.04 (s, 1H total), 4.53 (d, J=12.8 Hz,1H), 4.34 (d, J=12.8 Hz, 1H), 4.16 (s, 1H), 3.78, 3.77 (s, 3H total),3.28-3.01 (m, 11H), 2.88, 2.83 (s, 3H total), 2.42 (dd, J=13.2, 13.2 Hz,1H), 2.32-2.29 (m, 1H), 1.73-1.64 (m, 1H), 1.30-1.25 (m, 1H), 0.83 (t,J=8.8 Hz, 2H), 0.52-0.45 (m, 2H); MS (ESI) m/z 542.1 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.06 (m, 1H), 4.67, 4.29 (d, J=13.6 Hz, 1Htotal), 4.47 (dd, J=13.2, 13.2 Hz, 1H), 4.17 (s, 1H), 3.80 (s, 3H),3.29-3.02 (m, 13H), 2.48-2.33 (m, 2H), 1.75-1.65 (m, 1H), 1.44-1.36 (m,3H), 1.28-1.21 (m, 1H), 0.88-0.81 (m, 2H), 1.50-0.47 (m, 2H); MS (ESI)m/z 556.1 (M+H)

¹H NMR (400 MHz, CD₃OD) δ 7.43-7.38 (m, 5H), 6.88 (s, 1H), 4.28 (d,J=13.6 Hz, 1H), 4.16-4.11 (m, 2H), 3.62 (s, 3H), 3.30-3.03 (m, 11H),2.41-2.28 (m, 2H), 1.74-1.64 (m, 1H), 1.48 (s, 6H); MS (ESI) m/z 606.0(M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.51 (m, 5H), 6.88-6.85 (m, 1H), 4.30 (d,J=12.8 Hz, 1H), 4.20-4.15 (m, 1H), 3.93-3.89 (m, 1H), 3.81-3.60 (m, 6H),3.25-3.01 (m, 11H), 2.45-2.18 (m, 2H), 1.73-1.64 (m, 1H), 1.57-1.46 (m,6H); MS (ESI) m/z 620.0 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.53 (t, J=8.0 Hz, 2H), 7.44 (d, J=6.4 Hz,2H), 7.38-7.32 (m, 1H), 6.90, 6.80 (s, 1H total), 4.35-4.01 (m, 3H),3.64 (s, 3H), 3.54-3.50 (m, 1H), 3.24-3.01 (m, 12H), 2.43-2.30 (m, 2H),1.72-1.64 (m, 1H), 1.54 (d, J=12.4 Hz, 3H), 1.45 (d, J=13.2 Hz, 3H),1.30 (d, J=6.4 Hz, 3H); MS (ESI) m/z 634.0 (M+H)

¹H NMR (400 MHz, CD₃OD) δ 7.06 (s, 1H), 4.36 (d, J=13.2 Hz, 1H), 4.22(d, J=13.2 Hz, 1H), 4.16 (s, 1H), 3.70 (s, 3H), 3.31-3.02 (m, 10H), 2.43(dd, J=14.8, 14.4 Hz, 1H), 2.33-2.29 (m, 1H), 2.24-2.19 (m, 1H), 1.70(dd, J=13.6, 13.6 Hz, 1H), 1.35 (d, J=6.8 Hz, 3H), 1.06 (dd, J=6.8, 6.8Hz, 6H); MS (ESI) m/z 544.0 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.07, 7.05 (s, 1H total), 4.67 (d, J=12.8 Hz,1H), 4.23-4.11 (m, 2H), 3.84-3.80 (m, 3H), 3.31-3.03 (m, 13H), 2.49-2.20(m, 3H), 1.75-1.69 (m, 1H), 1.48-1.40 (m, 3H), 1.20-1.13 (m, 6H); MS(ESI) m/z 558.0 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.09, 7.06 (s, 1H total), 4.62, 4.22 (d,J=13.6 Hz, 1H total), 4.44 (dd, J=13.6, 13.6 Hz, 1H), 4.18 (s, 1H),3.83, 3.82 (s, 3H total), 3.30-3.03 (m, 12H), 2.48-2.25 (m, 3H),1.75-1.66 (m, 1H), 1.45-1.31 (m, 6H), 1.17-1.02 (m, 6H); MS (ESI) m/z572.0 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.09, 7.08 (s, 1H total), 4.58 (d, J=13.6 Hz,1H), 4.39 (dd, J=13.6, 13.6 Hz, 1H), 4.18 (s, 1H), 3.84, 3.82 (s, 3Htotal), 3.33-3.06 (m, 12H), 2.53-2.43 (m, 1H), 2.34 (m, 1H), 1.78-1.69(m, 1H), 1.56-1.46 (m, 6H), 1.40-1.35 (m, 3H); MS (ESI) m/z 544.1 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.15, 7.08 (s, 1H total), 4.52-4.51 (m, 2H),4.06-4.03 (m, 1H), 3.94-4.82 (m, 4H), 3.28-3.05 (m, 10H), 2.45 (dd,J=14.4, 14.4 Hz, 1H), 2.35-2.32 (m, 1H), 2.25-2.19 (m, 1H), 1.77-1.68(m, 1H), 1.12 (s, 9H); MS (ESI) m/z 574.0 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.09, 7.05 (s, 1H total), 4.80 (s, 2H),4.20-4.15 (m, 3H), 3.93 (s, 3H), 3.84-3.55 (m, 2H), 3.28-3.05 (m, 10H),2.46-2.39 (m, 2H), 1.76-1.67 (m, 1H), 1.57 (t, J=7.2 Hz, 2H), 1.46 (t,J=7.2 Hz, 1H), 1.28 (s, 3H), 1.03 (s, 6H); MS (ESI) m/z 602.1 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.05 (s, 1H), 4.57, 4.19 (d, J=13.2 Hz, 1Htotal), 4.44, 3.99 (d, J=13.2 Hz, 1H total), 4.14 (s, 1H), 3.80, 3.77(s, 3H total), 3.70-3.62 (m, 1H), 3.28-3.00 (m, 9H), 2.73 (s, 3H),2.49-2.27 (m, 2H), 1.74-1.63 (m, 1H), 1.52-1.40 (m, 6H); MS (ESI) m/z530.0 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.05 (s, 1H), 4.36 (d, J=13.6 Hz. 1H), 4.26(d, J=12.8 Hz, 1H), 4.17-4.04 (m, 5H), 3.92-3.82 (m, 5H), 3.28-3.04 (m,10H), 2.50-2.40 (m, 2H), 1.78-1.68 (m, 1H); MS (ESI) m/z 544.0 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.10 (s, 1H), 4.53 (d, J=13.6 Hz, 1H), 4.32(d, J=14.4 Hz, 1H), 4.22-4.17 (m, 4H), 3.92-3.88 (m, 1H), 3.82 (s, 3H),3.27-3.05 (m, 10H), 2.85 (s, 3H), 2.53-2.31 (m, 4H), 1.78-1.68 (m, 1H);MS (ESI) m/z 557.9

¹H NMR (400 MHz, CD₃OD) δ 7.08 (s, 1H), 4.43-4.38 (m, 2H), 4.27-4.21 (m,2H), 4.16-4.14 (m, 1H), 3.91-3.89 (m, 1H), 3.77-3.75 (m, 3H), 3.68-3.63(m, 1H), 3.31-3.04 (m, 12H), 2.51-2.45 (m, 2H), 2.36-2.30 (m, 2H),1.77-1.68 (m, 1H), 1.53-1.40 (m, 3H); MS (ESI) m/z 572.0 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.00 (s, 1H), 4.35 (d, J=14.0 Hz, 1H), 4.21(d, J=13.6 Hz, 1H), 4.10 (s, 1H), 3.90-3.86 (m, 2H), 3.75 (s, 3H),3.55-3.52 (m, 1H), 3.25-2.97 (m, 11H), 2.68-2.62 (m, 2H), 2.39 (dd,J=14.4, 14.4 Hz, 1H), 2.27-2.18 (m, 2H), 1.71-1.65 (m, 2H); MS (ESI) m/z558.0 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.02 (s, 1H), 4.66-4.62 (m, 1H), 4.47-4.36 (m,1H), 4.11 (s, 1H), 3.93-3.84 (m, 2H), 3.77 (s, 3H), 3.58-3.43 (m, 2H),3.26-2.98 (m, 11H), 2.88-2.84 (m, 4H), 2.42 (dd, J=13.6, 13.6 Hz, 1H),2.27-2.24 (m, 2H), 1.72-1.63 (m, 2H); MS (ESI) m/z 572.0 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.04, 7.03 (s, 1H total), 4.52-4.48 (m, 1H),4.34-4.25 (m, 1H), 4.11 (s, 1H), 3.93-3.87 (m, 2H), 3.77 (m, 3H),3.53-3.37 (m, 2H), 3.27-2.98 (m, 13H), 2.79-2.70 (m, 1H), 2.47-2.38 (m,1H), 2.27-2.21 (m, 2H), 1.72-1.55 (m, 2H), 1.43-1.38 (m, 3H); MS (ESI)m/z 586.0 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.03, 6.98 (s, 1H total), 4.31-4.13 (m, 2H),3.80-3.76 (m, 1H), 3.69 (s, 3H), 3.26-3.01 (m, 10H), 2.69 (s, 2H),2.43-2.02 (m, 5H), 1.71-1.55 (m, 2H), 1.50-1.33 (m, 4H); MS (ESI) m/z568.1 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.02, 6.95 (s, 1H total), 4.15 (d, J=13.2 Hz,1H), 3.97-3.91 (m, 1H), 3.82-3.67 (m, 4H), 3.24-3.00 (m, 13H), 2.71,2.68 (s, 3H total), 2.40-2.28 (m, 3H), 2.16-2.06 (m, 1H), 1.78-1.53 (m,5H), 1.37-1.31 (m, 1H); MS (ESI) m/z 582.1 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.04-6.97 (m, 1H), 4.57-4.12 (m, 3H),3.79-3.68 (m, 4H), 3.25-2.92 (m, 12H), 2.41-2.10 (m, 4H), 1.74-1.45 (m,6H), 1.40-1.32 (m, 5H); MS (ESI) m/z 596.1 (M+H).

¹H NMR (400 MHz, CD. OD) δ 7.03, 7.02 (s, 1H total), 4.66, 4.47 (d,J=13.2 Hz, 1H total), 4.31, 4.10 (d, J=13.2 Hz, 1H total), 4.12 (s, 1H),3.75, 3.74 (s, 3H total), 3.48-3.47 (m, 2H), 3.29-3.25 (m, 1H),3.05-2.89 (m, 9H), 2.41-2.32 (m, 2H), 2.29-2.22 (m, 1H), 2.13-2.09 (m,1H), 2.01-1.95 (m, 2H), 1.79-1.70 (m, 1H), 1.69-1.59 (m, 2H), 1.07-1.00(m, 3H), MS (ESI) m/z 556.1 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.08 (s, 1H), 4.39 (d, J=12.0 Hz, 1H), 4.25(d, J=14.4 Hz, 1H), 4.15 (s, 1H), 3.73 (s, 3H), 3.50 (t, J=14.4 Hz, 2H),3.26-3.23 (m, 2H), 3.07-2.91 (m, 9H), 2.40 (dd, J=14.4, 14.4 Hz, 1H),2.32-2.28 (m, 1H), 1.96-1.93 (m, 2H), 1.75-1.55 (m, 2H), 1.48-1.26 (m,6H), 0.97-0.90 (m, 3H); MS (ESI) m/z 584.1 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.06 (s, 1H), 4.40-4.36 (m, 1H), 4.25 (d,J=12.8 Hz, 1H), 4.11 (s, 1H), 3.76-3.71 (m, 3H total), 3.38-3.33 (m,2H), 3.28-3.21 (m, 2H), 3.07-2.89 (m, 9H), 2.63-2.58 (m, 1H), 2.39 (dd,J=14.4, 14.4 Hz, 1H), 2.28-2.25 (m, 1H), 1.97-1.94 (m, 1H), 1.87-1.81(m, 1H), 1.67-1.61 (m, 1H), 1.17-1.13 (m, 1H), 0.99-0.92 (m, 6H); MS(ESI) m/z 570.2 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.07 (s, 1H), 4.37 (d, J=13.2 Hz, 1H), 4.24(d, J=12.8 Hz, 1H), 4.14 (s, 1H), 3.76 (s, 3H), 3.55-3.48 (m, 2H),3.28-2.99 (m, 11H), 2.39 (dd, J=14.8, 14.4 Hz, 1H), 2.30-2.26 (m, 1H),1.96-1.92 (m, 2H), 1.87-1.32 (m, 5H), 0.92 (d, =7.2 Hz, 6H); MS (ESI)m/z 584.3 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.07 (s, 1H), 4.37 (d, J=12.8 Hz, 1H), 4.25(d, J=12.8 Hz, 1H), 4.14 (s, 1H), 3.72 (s, 3H), 3.57-3.49 (m, 2H),3.26-2.98 (m, 11H), 2.39 (dd, J=14.8, 14.4 Hz, 1H), 2.29-2.26 (m, 1H),1.95-1.93 (m, 2H), 1.70-1.57 (m, 3H), 1.41-1.32 (m, 1H), 0.92 (s, 9H));MS (ESI) m/z 598.4 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.29-7.21 (m, 4H), 7.02 (s, 1H), 4.37 (d,J=13.2 Hz, 1H), 4.24 (d, J=13.2, Hz, 1H), 4.17-4.12 (m, 2H), 3.77 (s,3H), 3.48 (dd, J=7.6, 7.6 Hz, 2H), 3.26-2.97 (m, 11H), 2.38 (dd, J=14.8,14.4 Hz, 1H), 2.28-2.25 (m, 1H), 1.67-1.61 (m, 1H); MS (ESI) m/z 590.1(M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.11, 7.09 (s, 1H total), 4.41 (dd, J=13.2,13.2 Hz, 1H), 4.28 (dd, J=13.2, 4.8 Hz, 1H), 4.14 (s, 1H), 3.79-3.72 (m,3H), 3.56-3.48 (m, 2H), 3.28-2.80 (m, 11H), 2.40 (dd, J=14.4, 14.0 Hz,1H), 2.30-2.27 (m, 1H), 2.06-1.93 (m, 1H), 1.88-1.80 (m, 1H), 1.68-1.52(m, 2H), 1.48-1.40 (m, 1H), 1.10 (d, J=7.2 Hz, 3H), 0.98 (s, 3H); MS(ESI) m/z 570.2 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.09 (s, 1H), 4.44 (d, J=13.2 Hz, 1H), 4.32(d, J=12.8 Hz, 1H), 4.14 (s, 1H), 3.76 (s, 3H), 3.67-3.60 (m, 2H),3.28-3.00 (m, 11H), 2.68-2.60 (m, 1H), 2.42 (dd, J=14.8, 14.4 Hz, 1H),2.30-2.27 (m, 1H), 2.20-2.10 (m, 2H), 1.97-1.91 (m, 2H), 1.73-1.64 (m,1H); MS (ESI) m/z 610.3 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.04 (s, 1H), 4.57 (d, J=11.6 Hz, 1H),4.39-4.30 (m, 2H), 4.13 (s, 1H), 3.75 (s, 3H), 3.52-3.45 (m, 1H),3.25-2.98 (m, 11H), 2.67-2.60 (m, 1H), 2.42-2.25 (m, 2H), 2.17-2.02 (m,2H), 1.97, 1.95 (s, 3H total), 1.67-1.60 (m, 1H); MS (ESI) m/z 585.4(M+H).

¹H NMR (400 MHz, CD₃OD) δ 6.96, 4.94 (s, 1H total), 4.56-4.50 (m, 1H),4.45-4.35 (m, 3H), 4.12-4.00 (m, 4H), 3.75-3.73 (m, 3H), 3.49-3.46 (m,3H), 3.21-2.98 (m, 9H), 2.42-2.36 (m, 1H), 1.68-1.60 (m, 1H); MS (ESI)m/z 544.2 (M+H).

S24-9-135:

MS (ESI) m/z 606.4 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.06 (s, 1H), 5.45 (d, J=52.8 Hz, 1H),4.61-4.56 (m, 1H), 4.41-4.38 (m, 1H), 4.13 (s, 1H), 3.74 (s, 3H),3.50-3.47 (m, 2H), 3.26-2.98 (m, 11H), 2.43-2.26 (m, 4H), 1.67-1.60 (m,1H); MS (ESI) m/z 546.2 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 6.89 (s, 1H), 4.21 (d, J=13.2 Hz, 1H),4.09-4.03 (m, 2H), 3.65 (s, 3H), 3.27-2.88 (m, 11H), 2.32-2.25 (m, 1H),2.19-2.16 (m, 1H), 1.66-1.52 (m, 8H), 1.21-1.12 (m, 4H), 0.91-0.88 (m,2H); MS (ESI) m/z 584.3 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.02, 7.01 (s, 1H total), 4.57 (d, J=12.8 Hz,1H), 4.40-4.30 (m, 1H), 4.13 (s, 1H), 3.75, 3.74 (s, 3H total),3.25-2.98 (m, 11H), 2.81, 2.79 (s, 3H total), 2.45-2.38 (m, 1H),2.29-2.26 (m, 1H), 1.71-1.65 (m, 9H), 1.40-1.20 (m, 4H), 1.02-0.96 (m,1H); MS (ESI) m/z 598.4 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 6.93 (s, 1H), 4.36 (d, J=13.2 Hz, 1H), 4.16(d, J=13.2 Hz, 1H), 4.14 (s, 1H), 3.66 (s, 3H), 3.16-2.88 (m, 13H),2.34-2.27 (m, 1H), 2.20-2.17 (m, 1H), 1.62-1.53 (m, 8H), 1.28-1.14 (m,7H), 0.91-0.86 (m, 2H); MS (ESI) m/z 612.4 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.01 (s, 1H), 4.78 (d, J=12.8 Hz, 1H), 4.17(d, J=13.2 Hz, 1H), 4.14 (s, 1H), 3.88-2.86 (m, 1H), 3.75 (s, 3H),3.70-3.67 (m, 2H), 3.45 (s, 3H), 3.41-3.37 (m, 2H), 3.27-2.98 (m, 9H),2.44-2.37 (m, 1H), 2.30-2.27 (m, 2H), 2.14-2.11 (m, 1H), 2.02-1.87 (m,2H), 1.70-1.62 (m, 1H); MS (ESI) m/z 572.2 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.02, 7.01 (s, 1H total), 4.58 (d, J=13.2 Hz,1H), 4.38-4.30 (m, 1H), 4.14 (s, 1H), 3.75, 3.74 (s, 3H total),3.25-2.98 (m, 11H), 2.81, 2.79 (s, 3H total), 2.44-2.37 (m, 1H),2.29-2.26 (m, 1H), 1.89-1.81 (m, 2H), 1.71-16 (m, 1H), 1.05-1.00 (m,3H); MS (ESI) m/z 530.3 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.01 (s, 1H), 4.46 (dd, J=13.6, 70.2 Hz, 1H),4.25 (dd, J=13.2, 10.8 Hz, 1H), 4.13 (s, 1H), 3.75 (s, 3H), 3.25-2.98(m, 13H), 2.44-2.37 (m, 1H), 2.30-2.26 (m, 1H), 1.82-1.79 (m, 2H),1.71-1.61 (m, 1H), 1.40-1.33 (m, 3H), 1.03-0.99 (m, 3H); MS (ESI) m/z544.4 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 6.98 (s, 1H), 4.31 (d, J=13.6 Hz, 1H), 4.17(d, J=13.6 Hz, 1H), 4.13 (s, 1H), 3.74 (s, 3H), 3.26-2.98 (m, 11H), 2.38(dd, J=14.8, 14.4 Hz, 1H), 2.29-2.25 (m, 1H), 1.80-1.73 (m, 2H),1.67-1.64 (m, 1H), 1.02 (t, J=7.2 Hz, 3H); MS (ESI) m/z 516.1 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.04, 7.02 (s, 1H total), 4.73, 4.60 (d,J=12.8 Hz, 1H total), 4.51, 4.44 (d, J=13.2 Hz, 1H total), 4.11 (s, 1H),3.78, 3.76 (s, 3H total), 3.24-2.98 (m, 11H), 2.52-2.44 (m, 1H),2.41-2.30 (m, 1H), 2.27-2.20 (m, 2H), 1.98-1.94 (m, 1H), 1.88-1.82 (m,1H), 1.80-1.60 (m, 2H), 1.31-1.29 (m, 1H), 1.22-1.18 (m, 1H), 1.12-1.08(m, 1H), 1.00-0.92 (m, 1H), 0.90-0.83 (m, 1H); MS (ESI) m/z 568.3 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.04 (s, 1H), 4.41 (d, J=13.6 Hz, 1H), 4.28(d, J=13.6, Hz, 1H), 4.09 (s, 1H), 3.74 (s, 3H), 3.63-3.58 (m, 4H),3.24-2.96 (m, 13H), 2.38 (dd, J=14.8, 14.0 Hz, 1H), 2.25-2.20 (m, 1H),2.18-2.10 (m, 4H), 1.66-1.60 (m, 1H); MS (ESI) m/z 571.3 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.12 (s, 1H), 4.60-4.53 (m, 1H), 4.42-4.37 (m,1H), 4.11 (s, 1H), 3.78-3.62 (m, 9H), 3.24-2.90 (m, 14H), 2.39 (dd,J=14.8, 14.0 Hz, 1H), 2.27-2.23 (m, 1H), 2.20-2.11 (m, 4H), 1.69-1.60(m, 1H); MS (ESI) m/z 585.4 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.14 (s, 1H), 4.58-4.52 (m, 1H), 4.41-4.38 (m,1H), 4.12 (s, 1H), 3.76-3.64 (m, 9H), 3.26-2.97 (m, 13H), 2.39 (dd,J=14.8, 14.4 Hz, 1H), 2.27-2.24 (m, 1H), 2.20-2.11 (m, 4H), 1.69-1.60(m, 1H), 1.43 (t, J=6.8 Hz, 3H); MS (ESI) m/z 599.4 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.36-7.28 (m, 5H), 7.05, 6.98 (s, 1H total),4.39-4.34 (m, 1H), 4.26-4.20 (m, 1H), 4.11 (s, 1H), 3.78, 3.73 (s, 3Htotal), 3.25-2.98 (m, 13H), 2.39 (dd, J=15.2, 14.4 Hz, 1H), 2.27-2.24(m, 1H), 1.72-1.62 (m, 1H); MS (ESI) m/z 578.3 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.30-7.26 (m, 5H), 7.04 (s, 1H), 4.66, 4.16(d, J=12.8 Hz, 1H total), 4.45-4.38 (m, 1H), 4.13 (s, 1H), 3.74, 3.72(s, 3H total), 3.45-3.34 (m, 2H), 3.20-2.97 (m, 11H), 2.89, 2.86 (s, 3Htotal), 2.42-2.33 (m, 1H), 2.29-2.19 (m, 1H), 1.65-1.58 (m, 1H); MS(ESI) m/z 592.3 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.33-7.24 (m, 5H), 7.06 (s, 1H), 4.59-4.54 (m,1H), 4.36 (d, J=13.6 Hz, 1H), 4.13 (s, 1H), 3.77-3.74 (m, 3H), 3.36-3.34(m, 2H), 3.22-2.98 (m, 13H), 2.45-2.38 (m, 1H), 2.30-2.15 (m, 1H),1.71-1.59 (m, 1H), 1.43-1.40 (m, 3H); MS (ESI) m/z 606.3 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.02, 7.01 (s, 1H total), 4.58, 4.21 (d,J=13.2 Hz, 1H total), 4.45, 4.02 (d, J=12.8 Hz, 1H total), 4.12 (s, 1H),3.74-3.73 (m, 3H), 3.24-2.97 (m, 10H), 2.73 (s, 3H), 2.45-2.37 (m, 1H),2.33-2.24 (m, 2H), 2.15-2.13 (m, 1H), 1.88-1.82 (m, 4H), 1.74-1.61 (m,3H); MS (ESI) m/z 556.3 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.10-7.01 (m, 1H), 4.48-4.19 (m, 2H), 4.12 (s,1H), 3.80-3.74 (m, 3H), 3.26-2.97 (m, 12H), 2.45-2.35 (m, 1H), 2.29-2.20(m, 2H), 2.15-2.10 (m, 1H), 1.87-1.80 (m, 4H), 1.73-1.64 (m, 3H), 1.34(t, J=7.2 Hz, 3H); MS (ESI) m/z 570.2 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.07-7.00 (m, 1H), 4.56-4.35 (m, 2H), 4.12 (s,1H), 3.93-3.84 (m, 1H), 3.79, 3.73 (s, 3H total), 3.16-2.61 (m, 13H),2.46-2.31 (m, 1H), 2.25-2.12 (m, 1H), 1.68-1.64 (m, 1H), 1.43-0.96 (m,9H); MS (ESI) m/z 558.2 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.08, 7.00 (s, 1H total), 4.63, 4.55 (dd,J=13.6 Hz, 1H total), 4.39-4.33 (m, 1H), 4.12 (s, 1H), 3.85-3.73 (m,3H), 3.36-3.33 (m, 1H), 3.22-2.96 (m, 11H), 2.46-2.38 (m, 1H), 2.25-2.15(m, 2H), 1.70-1.61 (m, 1H), 1.46-0.94 (m, 12H); MS (ESI) m/z 572.3(M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.06, 7.99 (s, 1H total), 4.31 (d, J=12.8 Hz,1H), 4.18 (d, J=13.6 Hz, 1H), 4.13 (s, 1H), 3.80, 3.75 (s, 3H total),3.27-2.99 (m, 10H), 2.42-2.35 (m, 1H), 2.30-2.27 (m, 1H), 2.20-2.16 (m,2H), 1.92-1.89 (m, 2H), 1.74-1.65 (m, 2H), 1.43-1.36 (m, 4H), 1.29-1.24(m, 1H); MS (ESI) m/z 556.2 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.02, 7.01 (s, 1H total), 4.61, 4.47 (d,J=12.8 Hz, 1H total), 4.13 (s, 1H), 3.96 (d, J=12.8 Hz, 1H), 3.77, 3.74(s, 3H total), 3.24-2.98 (m, 10H), 2.74 (s, 3H), 2.46-2.37 (m, 1H),2.32-2.29 (m, 1H), 2.18-2.10 (m, 2H), 2.00-1.96 (m, 2H), 1.74-1.51 (m,4H), 1.43-1.32 (m, 3H); MS (ESI) m/z 570.2 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.07, 7.01 (s, 1H total), 4.59, 4.43 (d,J=13.6 Hz, 1H total), 4.29, 4.09 (d, J=13.6 Hz, 1H total), 4.14 (s, 1H),3.77, 3.75 (s, 3H total), 3.28-2.99 (m, 12H), 2.46-2.40 (m, 1H),2.36-2.31 (m, 1H), 2.16-2.10 (m, 2H), 1.99-1.96 (m, 2H), 1.74-1.58 (m,4H), 1.41-1.23 (m, 6H); MS (ESI) m/z 584.3 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 6.98 (s, 1H), 4.31 (d, J=13.6 Hz, 1H), 4.18(d, J=13.2 Hz, 1H), 4.12 (s, 1H), 3.75 (s, 3H), 3.27-2.99 (m, 11H), 2.40(dd, J=15.2, 14.8 Hz, 1H), 2.28-2.25 (m, 1H), 1.72-1.63 (m, 1H), 1.36(t, J=7.2 Hz, 3H); MS (ESI) m/z 502.2 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.01 (s, 1H), 4.44 (d, J=13.6 Hz, 1H), 4.24(d, J=13.2 Hz, 1H), 4.11 (s, 1H), 3.75 (s, 3H), 3.25-2.97 (m, 13H), 2.41(dd, J=15.2, 14.8 Hz, 1H), 2.26 (ddd, J=13.6, 4.8, 2.8 Hz, 1H), 1.68(ddd, J=13.6, 13.6, 13.6 Hz, 1H), 1.39-1.36 (m, 6H); MS (ESI) m/z 530.2(M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.06, 6.99 (s, 1H total), 4.35 (d, J=13.2 Hz,1H), 4.25-4.18 (m, 1H), 4.09 (s, 1H), 3.79, 3.74 (s, 3H total),3.23-2.95 (m, 11H), 2.38 (dd, J=14.8, 14.4 Hz, 1H), 2.26-2.14 (m, 1H),1.90-1.80 (m, 6H), 1.65-1.56 (m, 3H), 0.79 (t, J=7.2 Hz, 3H); MS (ESI)m/z 570.3 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.01 (s, 1H), 4.47, 4.10 (d, J=12.8 Hz, 1Htotal), 4.33 (dd, J=12.8, 12.8 Hz, 1H), 4.10 (s, 1H), 3.75, 3.71 (s, 3Htotal), 3.24-2.95 (m, 11H), 2.83, 2.80 (m, 3H total), 2.40 (dd, J=14.8,14.8 Hz, 1H), 2.25-2.23 (m, 1H), 2.03-1.83 (m, 6H), 1.80-1.70 (m, 2H),1.69-1.59 (m, 1H), 0.88-0.80 (m, 3H); MS (ESI) m/z 584.3 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.00 (s, 1H), 4.42, 4.35 (d, J=13.2 Hz, 1Htotal), 4.20 (d, J=13.2 Hz, 1H), 4.09 (s, 1H), 3.74, 3.70 (s, 3H total),3.23-2.94 (m, 13H), 2.37 (dd, J=14.4, 13.2 Hz, 1H), 2.25-2.22 (m, 1H),1.84-1.85 (m, 6H), 1.75-1.71 (m, 2H), 1.69-1.58 (m, 1H), 1.43-1.37 (m,3H), 0.88-0.80 (m, 3H); MS (ESI) m/z 598.3 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.00 (s, 1H), 4.67, 4.25 (d, J=13.2 Hz, 1Htotal), 4.40 (dd, J=14.0, 14.0 Hz, 1H), 4.09 (s, 1H), 3.76, 3.72 (s, 3Htotal), 3.46-3.41 (m, 1H), 3.21-2.93 (m, 12H), 2.38 (dd, J=14.4, 14.4Hz, 1H), 2.25-2.22 (m, 1H), 1.98-1.82 (m, 6H), 1.76-1.71 (m, 2H),1.69-1.61 (m, 1H), 1.30-1.20 (m, 1H), 0.86-0.75 (m, 5H), 0.44 (dd,J=16.0, 4.4 Hz, 2H); MS (ESI) m/z 624.3 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.04, 6.97 (s, 1H total), 4.22 (d, J=12.4 Hz,1H), 4.10-4.04 (m, 2H), 3.77, 3.72 (s, 3H total), 3.23-2.94 (m, 9H),2.35 (dd, J=14.8, 14.8 Hz, 1H), 2.25-2.22 (m, 1H), 1.78 (s, 2H),1.67-1.58 (m, 1H), 1.52 (s, 6H), 1.08 (s, 9H); MS (ESI) m/z 586.3 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.05, 6.98 (s, 1H total), 4.71, 4.60 (d,J=12.8 Hz, 1H total), 4.10 (m, 1H), 3.93-3.87 (m, 1H), 3.77-3.71 (m,3H), 3.21-2.95 (m, 9H), 2.66 (s, 3H), 2.41 (dd, J=14.4, 14.4 Hz, 1H),2.33-2.23 (m, 1H), 2.00-1.94 (m, 1H), 1.81 (d, J=14.0 Hz, 1H), 1.66-1.57(m, 7H), 1.12 (s, 9H); MS (ESI) m/z 600.4 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.09, 7.08 (s, 1H total), 4.70, 4.55 (d,J=13.2 Hz, 1H total), 4.28, 4.13 (d, J=13.2 Hz, t, J=6.4 Hz, 2H total),3.77, 3.76 (s, 3H total), 3.54-3.47 (m, 1H), 3.27-2.99 (m, 10H), 2.42(dd, J=14.4, 14.4 Hz, 1H), 2.30-2.27 (m, 1H), 2.00-1.88 (m, 2H),1.72-1.66 (m, 7H), 1.15 (s, 9H), 1.08 (t, J=7.2 Hz, 3H); MS (ESI) m/z614.3 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.10, 7.06 (s, 1H total), 4.70, 4.55 (d,J=13.2 Hz, 1H total), 4.28, 4.13 (d, J=13.2 Hz, t, J=6.4 Hz, 2H total),3.77, 3.76 (s, 3H total), 3.54-3.47 (m, 1H), 3.27-2.99 (m, 10H), 2.42(dd, J=14.4, 14.4 Hz, 1H), 2.30-2.27 (m, 1H), 2.00-1.88 (m, 2H),1.72-1.66 (m, 7H), 1.15 (s, 9H), 1.08 (t, J=7.2 Hz, 3H); MS (ESI) m/z640.4 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.01, 6.99 (s, 1H total), 4.57-4.36 (m, 1H),4.33-4.12 (m, 1H), 4.15, 4.13 (s, 1H total), 3.77, 3.73 (s, 3H total),3.58-3.40 (m, 1H), 3.24-2.96 (m, 11H), 2.44-2.37 (m, 1H), 2.28-2.24 (m,1H), 2.04-1.84 (m, 2H), 1.70-1.60 (m, 1H), 1.47-1.36 (m, 3H), 1.06-0.96(m, 4H), 0.76-0.68 (m, 2H), 0.42-0.31 (m, 2H); MS (ESI) m/z 584.3 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.02, 7.01 (s, 1H total), 4.56-4.39 (m, 1H),4.12 (s, 1H), 4.02-3.93 (m, 1H), 3.78-3.74 (m, 3H), 3.35-3.32 (m, 1H),3.26-2.98 (m, 9H), 2.74, 2.73 (s, 3H total), 2.46-2.33 (m, 1H),2.28-2.25 (m, 1H), 1.99-1.92 (m, 2H), 1.82-1.60 (m, 1H), 1.47-1.40 (m,3H), 1.09-1.00 (m, 3H); MS (ESI) m/z 544.2 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.03-7.00 (m, 1H), 4.53-4.49 (m, 1H),4.37-4.34 (m, 1H), 4.12 (s, 1H), 3.77-3.73 (m, 3H), 3.42-3.34 (m, 1H),3.26-2.97 (m, 11H), 2.42 (dd, J=14.4, 14.4 Hz, 1H), 2.28-2.25 (m, 1H),1.97-1.92 (m, 1H), 1.72-1.61 (m, 2H), 1.48-1.46 (m, 6H), 1.08-0.98 (m,3H); MS (ESI) m/z 558.1 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 6.97 (s, 1H), 4.12-4.09 (m, 2H), 3.85 (d,J=13.2 Hz, 1H), 3.74 (s, 3H), 3.25-2.96 (m, 9H), 2.46-4.38 (m, 3H),2.27-2.24 (m, 1H), 2.12-1.93 (m, 4H), 1.69-1.60 (m, 4H); MS (ESI) m/z542.2 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.03 (s, 1H), 4.31, 4.03 (d, J=12.4 Hz, 1Htotal), 4.21, 3.88 (d, J=13.2 Hz, 1H total), 4.13 (s, 1H), 3.78, 3.73(s, 3H total), 3.25-2.98 (m, 9H), 2.66-2.61 (m, 3H), 2.56-2.29 (m, 2H),2.26-2.17 (m, 2H), 2.05-2.00 (m, 1H), 1.94-1.88 (m, 2H), 1.71-1.60 (m,4H); MS (ESI) m/z 556.2 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.07, 7.06 (s, 1H total), 4.50, 4.16 (d,J=13.6 Hz, 1H total), 4.31-4.29 (m, 1H), 4.12 (s, 1H), 3.76, 3.75 (s, 3Htotal), 3.26-2.96 (m, 11H), 2.61-2.56 (m, 1H), 2.43-2.25 (m, 3H),2.09-2.04 (m, 1H), 1.95-1.70 (m, 3H), 1.70-1.61 (m, 4H), 0.93-0.90 (m,1H), 0.71-0.67 (m, 2H), 0.37-0.34 (m, 2H); MS (ESI) m/z 596.3 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 6.96 (s, 1H), 4.20-4.12 (m, 2H), 4.06 (d,J=13.6 Hz, 1H), 3.82-3.79 (m, 1H), 3.74 (s, 3H), 3.26-2.98 (m, 9H),2.42-2.20 (m, 6H), 1.96-1.89 (m, 2H), 1.71-1.62 (m, 1H); MS (ESI) m/z528.1 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.04, 7.03 (s, 1H total), 4.36-4.32 (m, 1H),4.16-4.13 (m, 1H), 4.02-3.98 (m, 1H), 3.81, 3.76 (s, 3H total),3.26-2.98 (m, 12H), 2.66-2.02 (m, 6H), 1.84-1.60 (m, 3H), 1.16-1.14 (m,1H), 0.80-0.77 (m, 2H), 0.41-0.38 (m, 2H); MS (ESI) m/z 582.1 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.14, 7.06 (s, 1H total), 4.55-4.78 (m, 1H),4.33-4.29 (m, 1H), 4.12, 3.98 (s, 1H total), 3.82-3.74 (m, 3H),3.24-2.98 (m, 13H), 2.38 (dd, J=12.8, 12.8 Hz, 1H), 2.29-2.26 (m, 1H),2.18-2.15 (m, 1H), 1.72-1.62 (m, 1H), 1.46-1.42 (m, 3H), 1.06-1.02 (m,9H); MS (ESI) m/z 572.2 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.14-7.06 (m, 1H), 4.76, 4.32 (d, J=13.6 Hz,1H total), 4.61-4.47 (m, 1H), 4.12, 3.89 (s, 1H total), 3.82-3.78 (m,3H), 3.25-2.98 (m, 13H), 2.42-2.15 (m, 2H), 1.72-1.63 (m, 1H), 1.32-2.28(m, 1H), 1.04, 1.00 (s, 9H total), 0.87-0.82 (m, 2H), 0.53-0.48 (m, 2H);MS (ESI) m/z 598.3 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.70-7.51 (m, 5H), 6.98-6.86 (m, 1H),4.62-4.35 (m, 2H), 4.13 (s, 1H), 4.10-3.78 (m, 1H), 3.51-3.57 (m, 3H),3.22-2.87 (m, 9H), 2.80, 2.79, 2.68, 2.67 (s, 3H total), 2.40-2.23 (m,2H), 1.88-1.80 (m, 3H), 1.68-1.58 (m, 1H); MS (ESI) m/z 592.0 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.67-7.52 (m, 5H), 6.95, 6.90, 6.81, 6.74 (s,1H total), 4.68-4.61 (m, 1H), 4.48-4.17 (m, 1.5H), 4.13, 4.11 (s, 1Htotal), 4.10-4.00 (m, 0.5H), 3.48, 3.45, 3.41, 3.39 (s, 3H total),3.21-2.88 (m, 11H), 2.39-2.22 (m, 2H), 1.85-1.76 (m, 3H), 1.68-1.58 (m,1H), 1.45-1.34 (m, 3H); MS (ESI) m/z 606.1 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.02 (s, 1H), 4.67-4.39 (m, 3H), 4.12 (s, 1H),3.72 (s, 3H), 3.26-3.20 (m, 2H), 3.05-2.89 (m, 9H), 2.49-2.40 (m, 1H),2.38-2.32 (m, 1H), 2.29-2.22 (m, 1H), 2.17-2.11 (m, 2H), 2.07-2.00 (m,1H), 1.70-1.60 (m, 1H); MS (ESI) m/z 596.1 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.82-755 (m, 5H), 6.89 (s, 1H), 4.22, 3.95 (d,J=−12.4 Hz, total 1H), 4.13 (s, 1H), 3.11-3.00 (m, 11H), 2.83, 2.80 (s,total 3H), 2.37-2.25 (m, 2H), 1.98-1.88 (m, 6H), 1.69-1.60 (m, 1H); MS(ESI) m/z 606.1 (M+H).

S24-9-182:

MS (ESI) m/z 592.3 (M+H).

Example 25 Synthesis of Compounds Via Scheme 25

The following compounds were prepared according to Scheme 25.

Compound S15-5 (20 g, 62.5 mmol, 1.0 equiv), 2, 4, 6Trivinylcyclotriboroxane-pyridine complex (7.8 g, 31.25 mmol, 0.50equiv), Pd(PPh₃)₄ (2.2 g, 1.88 mmol, 0.030 equiv) and K₂CO₃ (17.25 g,125 mmol, 2.0 equiv) was added to vessel in 1.4 dioxane:H₂O (3:1, V:V).The mixture was bubbled with N₂ to remove O₂ for 6 times. The mixturewas heated to reflux for 19 h. The mixture was concentrated. The residuepartitioned between EA and water. The organic layer was dried overNa₂SO₄ and evaporated to dryness. The crude compound was purified bycolumn chromatography on silica gel elute with (PE:EA=200:1→100:1→50:1),yielded (88.3%) 14.8 g compound S25-1 as a light yellow solid. ¹H NMR(400 MHz, CDCl₃) δ 7.38-7.34 (m, 2H), 7.27-7.16 (m, 3H), 6.83-6.76 (m,2H), 6.65-6.60 (m, 1H), 5.72 (d, J=17.6 Hz, 1H), 5.25 (d, J=11.2 Hz,1H), 3.83 (s, 3H), 2.38 (s, 3H); MS (ESI) m/z 269.1 (M+H).

An ozone-enriched steam of oxygen was bubbled through a cold (−78 C)solution of compound S25-1 (21 g, 78.3 mmol, 1.0 equiv) in anhydrousCH₂Cl₂ until it turned light blue. The reaction was followed by TLC. Thesolution was purged with argon at −78 C for 10 min to remove the excessO₃. CH₃SCH₃ (50 mL) was added into the reaction mixture and stirred for5 hour from −78 C to 25 C. The reaction was concentrated. he crudecompound was purified by column chromatography on silica gel elute with(PE:EA=100:1→50:→30:1) to yield (61.6%) 13 g compound S25-2 as a lightyellow solid. ¹H NMR (400 MHz, CDCl₃) δ 9.97 (s, 1H), 7.46-7.41 (m, 2H),7.36-7.22 (m, 5H), 3.92 (s, 3H), 2.51 (s, 3H); MS (ESI) m/z 271.1 (M+H).

Compound S25-3 (1.8 g, 6.62 mmol, 1 equiv) was dissolved in HOAc.Bromine (1.6 mL, 26.5 mmol, 4 equiv) was added dropwise into thesolution. The reaction mixture was stirred for 1 hour at rt. The mixturewas concentrated. The residue was extracted with EA and a saturatedNaHCO₃. The organic layer was washed with brine and water in return,dried over Na₂ SO₄ and concentrated to dryness. To afford 1.9 g compoundS25-3 as a light yellow solid.

BBr₃ (4.9 g, 1.9 mL, 19.5 mmol, 1.5 equiv) was added to a CH₂Cl₂solution (30 mL) of S25-3 (3.5 g, 13.0 mmol, 1.0 equiv) at −78 C. Thereaction was stirred from −78° C. to 25° C. for 1.5 h, quenched withsaturated NaHCO₃ and the reaction mixture was extracted with EtOAc. Thecombined EtOAc extracts were dried (Na₂SO₄) and concentrated to yield3.3 g of crude S25-4.

K₂CO₃ (3.6 g, 26.0 mmol, 2.0 equiv) and BnBr (4.2 g, 26.0 mmol, 2.0equiv) were added to a solution of compound S25-4 (3.3 g, 13.0 mmol, 1.0equiv) in DMF (15 mL). The reaction mixture was stirred at rt for 2 h.The reaction mixture was filtered and washed with EtOAc. Water (150 mL)was added into it and extracted with EtOAc. The organic layer was driedover Na₂SO₄ and concentrated. The crude compound was purified by columnchromatography on silica gel elute with (PE:EA=100: 1-50:1), yielded(61.7% for 3 steps) 3.5 g compound S25-5 as a light yellow solid. ¹H NMR(400 MHz, CDCl₃) δ 10.43 (s, 1H), 7.46-7.30 (m, 9H), 7.08-7.05 (m, 2H),5.17 (s, 2H), 2.52 (s, 3H); MS (ESI) m/z 425.1 (M+H).

Compound S25-5 (5 g, 11.8 mmol, 1.0 equiv) in anhydrous DMF was addedCH₃O₂CCF₂SO₂F (11.3 g, 59 mmol, 5.0 equiv) and CuI (4.5 g, 23.6 mmol,2.0 equiv) in obturator. The reaction was heated to 100 C for 20 h. Themixture was filtered and washed with EA. The solution was concentratedand extracted with EA and water. The organic layer was dried over Na₂SO₄ and concentrated to the crude compound S25-6 as brown oil (7 g). ¹HNMR (400 MHz, CDCl₃) δ 10.35-10.32 (m, 1H), 7.40-7.28 (m, 9H), 7.02-6.83(m, 2H), 5.17 (s, 2H), 2.55-2.51 (m, 3H); MS (ESI) m/z 415.1 (M+H).

Compound S25-6 (7 g crude, 11.8 mmol, 1.0 equiv) in MeOH was addedHC(OMe)₃ (3.6 g, 35.4 mmol, 3.0 equiv) and TsOH (0.23 g, 1.18 mmol, 0.1equiv). The reaction was heated to reflux for 18 h. The mixture wasconcentrated. The residue was extracted with EA and water. The organiclayer was dried over Na₂SO₄ and concentrated. The crude compound waspurified by column chromatography on silica gel elute with(PE:EA=100:1→50:1) to yield (90.6% for 2 steps) 4.9 g compound S25-7 asa light yellow oil. ¹H NMR (400 MHz, CDCl₃) δ 7.45-7.30 (m, 9H),7.08-6.90 (m, 2H), 5.60 (s, 1H), 5.20 (s, 2H), 3.73 (s, 6H), 2.56-2.51(m, 3H); MS (ESI) m/z 461.1 (M+H).

To diisopropylamine (0.414 mL, 2.5 mmol, 5.0 equiv) in THF at −78° C.was added nBuLi (1.04 mL, 2.50 M/hexane, 2.5 mmol, 5.0 equiv) and TMEDA(1.04 mL, 2.5 mmol, 5.0 equiv) at −78° C. dropwise. The reaction wasstirred at −78° C. for 30 min. Compound S25-7 (460 mg, 1.25 mmol, 2.5equiv) in THF was added to the reaction mixture dropwise at −78 C. Theresulting deep-red solution was stirred at −78° C. 15 min and added withthe enone (240 mg 0.50 mmol, 1.0 equiv) in THF. The deep-red solutionwas gradually warmed up with stirring from −78° C. to 0° C. over aperiod of 30 min. and quenched with aqueous saturated ammonium chloride(100 mL). The yellow-green mixture was extracted with EtOAc two times.The combined EtOAc extracts were dried (Na₂ SO₄) and concentrated toyield the crude product. Flash column chromatography on silica gel with0%, 5%, 10%, and 20% EtOAc/hexane sequentially yielded the desiredproduct S25-8 as a light-yellow solid (380 mg, 89%). ¹H NMR (400 MHz,CDCl₃) δ 15.65 (s, 1H), 7.46-7.22 (m, 11H), 5.49 (s, 1H), 5.30 (s, 2H),5.25 (s, 2H), 3.91 (d, J=10.8 Hz, 1H), 3.29 (s, 3H), 3.20 (s, 3H),2.85-2.62 (m, 2H), 2.53-2.35 (m, 9H), 2.10-2.04 (m, 1H), 0.88 (s, 9H),0.20 (s, 3H), 0.09 (s, 3H); MS (ESI) m/z 849.1 (M+H).

Compound S25-8 (0.3 g, 0.354 mmol) was dissolved in DCM (3 mL) andaqueous TFA (3 mL) was added dropwise. The yellow solution was stirredat rt for 1 h. The reaction was followed by LC-MS. The solution wasconcentrated. The residue was extracted with EA and water. The combinedEtOAc extracts were dried (Na₂SO₄) and concentrated to yield the crudeproduct S25-9.

Compound S25-9 (50 mg crude, 0.059 mmol, 1.0 equiv) was dissolved in1,2-dichloroethane (1.0 mL). Pyrroliding (0.295 mmol, 5.0 equiv) andacetic acid (20 μL, 0.36 mmol, 6.0 equiv) were added. After stirring atrt for 1 h, sodium triacetoxyborohydride (37 mg, 0.177 mmol, 3.0 equiv)was added. Stirring was continued overnight. The reaction mixture waspoured into saturated aqueous NaHCO₃ and extracted three times withdichloromethane. The combined organic extracts were washed with brine,dried over sodium sulfate, and concentrated to give the crudeintermediate S25-10-1, which was used directly in the next step withoutfurther purification.

Compound S25-10-1 (50 mg, crude, 0.059 mmol, 1 equiv) was dissolved inTHF (10 mL) and aqueous HF (40%, 10 mL) was added dropwise. The yellowsolution was stirred at rt for 1 h. The resulting deep-red solution wasslowly added into an aqueous K₂HPO₄ solution with stirring. The pH ofthe mixture was adjusted by aqueous K₂HPO₄ solution to about 8. Theyellow mixture was extracted with EtOAc two times. The combined EtOAcextracts were dried (Na₂SO₄) and concentrated to yield the crudeintermediate.

The above crude intermediate (50 mg, crude, 0.059 mmol, 1 equiv) wasdissolved in HPLC grade MeOH (10 mL). HCl/MeOH (1.0 mL, 4N) and 10% Pd—C(50 mg, 0.046 mmol, 0.78 equiv) were added. The mixture was purged withhydrogen by bubbling hydrogen through with gentle stirring for 5 min.The reaction was then vigorously stirred under hydrogen balloon at rtfor 1 hr. LC-MS analysis indicated complete reaction. The catalyst wasfiltered and concentrated to yield the crude product as a deep-yellowsolid. The crude compound was purified by prep-HPLC on a Polymerx columnto yield the desired product S25-11-1 as a yellow solid afterfreeze-drying (7 mg, 21%). ¹H NMR (400 MHz, CD₃OD) δ 7.26 (s, 1H), 4.71(d, J=14.0 Hz, 1H), 4.49 (d, J=14.0 Hz, 1H), 4.14 (s, 1H), 3.74-3.59 (m,2H), 3.30-2.96 (m, 11H), 2.69-2.57 (m, 1H), 2.26-2.01 (m, 5H), 1.69-1.59(m, 1H); MS (ESI) m/z 566.1 (M+H).

The following final compounds were prepared from S25-9 by reductiveamination with various amines, followed by aqueous HF treatment andhydrogenation under similar conditions described for S25-11-1.

S25-11-2

¹H NMR (400 MHz, CD₃OD) δ 7.17 (s, 1H), 4.43 (d, J=14.0 Hz, 1H), 4.32(d, J=14.0 Hz, 1H), 4.13 (s, 1H), 3.16 (t, J=8.4 Hz, 2H), 3.09-2.96 (m,9H), 2.65-2.62 (m, 1H), 2.26-2.22 (m, 1H), 1.77-1.63 (m, 3H), 1.49-1.43(m, 2H), 1.02 (t, J=7.2 Hz, 3H); MS (ESI) m/z 568.2 (M+H).

S25-11-3:

¹H NMR (400 MHz, CD₃OD) δ 7.25 (s, 1H), 4.79-4.67 (m, 1H), 4.45-4.29 (m,1H), 4.15 (s, 1H), 3.26-2.97 (m, 11H), 2.90-2.81 (m, 3H), 2.69-2.57 (m,1H), 2.28-2.24 (m, 1H), 1.83-1.75 (m, 2H), 1.69-1.60 (m, 1H), 1.47-1.38(m, 2H), 1.00 (t, J=7.2 Hz, 3H); MS (ESI) m/z 582.1 (M+H).

S25-11-4:

¹H NMR (400 MHz, CD₃OD) δ 7.21 (s, 1H), 4.65-4.55 (m, 1H), 4.53-4.45 (m,1H), 4.12 (s, 1H), 3.37-3.33 (m, 2H), 3.26-2.95 (m, 11H), 2.68-2.57 (m,1H), 2.26-2.20 (m, 1H), 1.82-1.60 (m, 3H), 1.44-1.35 (m, 5H), 1.01 (t,J=7.2 Hz, 3H); MS (ESI) m/z 596.3 (M+H).

S25-11-5:

¹H NMR (400 MHz, CD₃OD) δ 7.30-7.21 (m, 5H), 4.51 (d, J=13.6 Hz, 1H),4.40 (d, J=14.0 Hz, 1H), 4.27-4.24 (m, 1H), 4.12 (s, 1H), 3.66-3.47 (m,2H), 3.24-2.95 (m, 11H), 2.65-2.61 (m, 1H), 2.25-2.22 (m, 1H), 1.65-1.60(m, 1H); MS (ESI) m/z 628.2 (M+H).

S25-11-6:

¹H NMR (400 MHz, CD₃OD) δ 7.14 (s, 1H), 4.29 (d, J=14.0 Hz, 1H), 4.17(d, J=14.8 Hz, 1H), 4.13 (s, 1H), 3.93-3.89 (m, 1H), 3.09-2.95 (m, 9H),2.65-2.60 (m, 1H), 2.42-2.22 (m, 5H), 1.98-1.89 (m, 2H), 1.65-1.60 (m,1H); MS (ESI) m/z 566.2 (M+H).

S25-11-7:

¹H NMR (400 MHz, CD₃OD) δ 7.16 (s, 1H), 4.44 (d, J=14.0 Hz, 1H), 4.35(d, J=14.0 Hz, 1H), 4.12 (s, 1H), 3.23-2.96 (m, 11H), 2.66-2.62 (m, 1H),2.25-2.21 (m, 1H), 1.70-1.62 (m, 3H), 1.05 (s, 9H); MS (ESI) m/z 596.0(M+H).

S25-11-8:

¹H NMR (400 MHz, CD₃OD) δ 7.16 (s, 1H), 4.50 (d, J=15.2 Hz, 1H), 4.38(d, J=15.2 Hz, 1H), 4.13 (s, 1H), 3.78-3.68 (m, 3H), 3.37-3.31 (m, 2H),3.26-3.25 (m, 1H), 3.10-2.92 (m, 8H), 2.66-2.61 (m, 1H), 2.26-2.22 (m,1H), 1.69-1.63 (m, 1H), 1.21 (d, J=6.4 Hz, 6H); MS (ESI) m/z 598.1(M+H).

S25-11-9:

¹H NMR (400 MHz, CD₃OD) δ 7.08 (s, 1H), 4.35 (d, J=14.4 Hz, 1H), 4.23(d, J=13.6 Hz, 1H), 4.03 (s, 1H), 3.09 (t, J=8.4 Hz, 2H), 2.95-2.86 (m,9H), 2.52-2.48 (m, 1H), 2.16-2.13 (m, 1H), 1.64-1.44 (m, 4H), 0.90 (d,J=6.4 Hz, 6H); MS (ESI) m/z 582.1 (M+H).

S25-11-10:

¹H NMR (400 MHz, CD₃OD) δ 7.15 (s, 1H), 4.36-4.29 (m, 2H), 4.04 (s, 1H),3.03-2.86 (m, 11H), 2.56-2.49 (m, 1H), 2.17-2.12 (m, 1H), 1.60-1.50 (m,1H), 1.00 (s, 9H); MS (ESI) m/z 582.2 (M+H).

S25-11-11:

¹H NMR (400 MHz, CD₃OD) δ 7.25 (s, 1H), 4.56 (d, J=14.0 Hz, 1H), 4.39(d, J=14.0 Hz, 1H), 4.13 (s, 1H), 3.19-2.90 (m, 10H), 2.69-2.59 (m, 1H),2.25-2.22 (m, 1H), 1.69-1.59 (m, 1H), 1.39 (d, J=8.8 Hz, 3H), 1.05 (s,9H); MS (ESI) m/z 596.2 (M+H).

S25-11-12:

¹H NMR (400 MHz, CD₃OD) δ 7.22, 7.20 (s, 1H total), 4.43-4.26 (m, 2H),4.13 (s, 1H), 3.64-3.62 (m, 1H), 3.25-2.95 (m, 9H), 2.67-2.57 (m, 2H),2.35-2.11 (m, 3H), 1.68-1.43 (m, 7H), 1.18-1.12 (m, 1H); MS (ESI) m/z606.3 (M+H).

S25-11-13:

¹H NMR (400 MHz, CD₃OD) δ 7.18 (s, 1H), 4.40 (d, J=14.0 Hz, 1H), 4.31(d, J=14.0 Hz, 1H), 4.14 (s, 1H), 3.25-2.98 (m, 11H), 2.78-2.55 (m, 2H),2.26-2.18 (m, 3H), 2.08-1.85 (m, 4H), 1.70-1.58 (m, 1H); MS (ESI) m/z580.3 (M+H).

S25-11-14:

¹H NMR (400 MHz, CD₃OD) δ 7.05 (s, 1H), 4.32 (d, J=14.0 Hz, 1H), 4.20(d, J=14.4 Hz, 1H), 4.00 (s, 1H), 3.15-2.82 (m, 11H), 2.51-2.43 (m, 1H),2.13-2.09 (m, 1H), 1.55-1.45 (m, 1H), 1.10-0.99 (m, 1H), 0.65-0.58 (m,2H), 0.35-0.27 (m, 2H); MS (ESI) m/z 566.1 (M+H).

S25-11-15:

¹H NMR (400 MHz, CD₃OD) δ 7.19 (s, 1H), 4.42-4.29 (m, 2H), 4.13 (s, 1H),3.17-2.95 (m, 10H), 2.65-2.58 (m, 1H), 2.26-2.22 (m, 1H), 1.96-1.90 (m,1H), 1.68-1.58 (m, 2H), 1.42-1.37 (m, 3H), 1.02 (t, J=7.2 Hz, 3H); MS(ESI) m/z 568.2 (M+H).

S25-11-16:

¹H NMR (400 MHz, CD₃OD) δ 7.33, 7.26 (s, 1H total), 4.57-4.29 (m, 2H),4.13 (s, 1H), 3.62-3.50 (m, 1H), 3.22-2.84 (m, 12H), 2.68-2.55 (m, 1H),2.26-2.22 (m, 1H), 2.07-1.83 (m, 2H), 1.68-1.44 (m, 3H), 1.12, 1.11 (s,3H total), 1.04, 1.02 (s, 3H total); MS (ESI) m/z 608.3 (M+H).

S25-11-17:

¹H NMR (400 MHz, CD₃OD) δ 7.20 (s, 1H), 6.38 (tt, J=6.4, 54.0 Hz, 1H),4.56 (dd, J=1.6, 14.0 Hz, 1H), 4.46 (dd, J=1.6, 14.8 Hz, 1H), 4.14 (s,1H), 3.77-3.67 (m, 2H). 3.21-2.98 (m, 9H), 2.66-2.58 (m, 1H). 2.27-2.21(m, 1H), 1.69-1.59 (m, 1H); MS (ESI) m/z 575.9 (M+H).

S25-11-18:

¹H NMR (400 MHz, CD₃OD) δ 7.21 (s, 1H), 4.48-4.32 (m, 2H), 4.13 (s, 1H),3.94-3.88 (m, 2H), 3.79-3.75 (m, 1H), 3.59-3.55 (m, 1H), 3.25-2.96 (m,11H), 2.70-2.58 (m, 2H), 2.27-2.21 (m, 2H), 1.75-1.63 (m, 2H); MS (ESI)m/z 596.0

S25-11-19:

¹H NMR (400 MHz, CD₃OD) δ 7.23 (s, 1H), 4.41 (d, J=14.4 Hz, 1H), 4.26(d, J=14.8 Hz, 1H), 4.13 (s, 1H), 3.25-2.95 (m, 9H), 2.69-2.58 (m, 1H),2.27-2.22 (m, 1H), 1.87-1.77 (m, 2H), 1.69-1.59 (m, 1H), 1.42 (s, 6H),1.03 (t, J=7.2 Hz, 3H); MS (ESI) m/z 582.0 (M+H).

S25-11-20:

¹H NMR (400 MHz, CD₃OD) δ 7.21 (s, 1H), 4.69 (d, J=14.8 Hz, 1H), 4.56(d, J=14.8 Hz, 1H), 4.14 (s, 1H), 3.23-2.96 (m, 9H), 2.69-2.57 (m, 1H),2.28-2.22 (m, 1H), 1.69-1.54 (m, 2H), 1.11-1.05 (m, 2H), 0.83-0.76 (m,2H), 0.74-0.69 (m, 2H), 0.41-0.35 (m, 2H); MS (ESI) m/z 592.0 (M+H).

S25-11-21:

¹H NMR (400 MHz, CD₃OD) δ 7.41 (s, 4H), 7.32 (s, 1H), 4.78-4.67 (m, 6H),4.13 (s, 1H), 3.22-2.95 (m, 9H), 2.67-2.58 (m, 1H), 2.25-2.22 (m, 1H),1.68-1.59 (m, 1H); MS (ESI) m/z 614.0 (M+H).

S25-11-22:

¹H NMR (400 MHz, CD₃OD) δ 7.18 (s, 1H). 4.51 (d, J=13.6 Hz, 1H), 4.40(d, J=13.2 Hz, 1H), 4.13 (s, 1H), 3.23-2.95 (m, 9H), 2.67-2.55 (m, 1H),2.25-2.22 (m, 1H), 1.67-1.53 (m, 1H), 1.52 (s, 3H), 1.18-1.12 (m, 2H),0.88-0.82 (m, 2H); MS (ESI) m/z 566.0 (M+H).

S25-11-23:

¹H NMR (400 MHz, CD₃OD) δ 7.24 (s, 1H), 4.75-4.63 (m, 1H), 4.44-4.27 (m,1H), 4.14 (s, 1H), 3.46-3.34 (m, 2H), 3.20-2.95 (m, 9H), 2.85 (d, J=14.8Hz, 3H), 2.68-2.55 (m, 1H), 2.26-2.22 (m, 1H), 1.68-1.59 (m, 1H), 1.41(t, J=7.2 Hz, 3H); MS (ESI) m/z 554.0 (M+H).

S25-11-24:

¹H NMR (400 MHz, CD₃OD) δ 7.21 (s, 1H), 4.59 (d, J=14.0 Hz, 1H), 4.45(d, J=14.4 Hz, 1H), 4.13 (s, 1H), 3.35-3.32 (m, 2H), 3.25-2.95 (m, 11H),2.66-2.60 (m, 1H), 2.26-2.20 (m, 1H), 1.68-1.58 (m, 1H), 1.39-1.32 (m,6H); MS (ESI) m/z 568.0 (M+H).

S25-11-25:

¹H NMR (400 MHz, CD₃OD) δ 7.20 (s, 1H). 4.64-4.59 (m, 1H). 4.51-4.45 (m,1H), 4.12 (s, 1H), 3.35-3.32 (m, 2H), 3.20-2.95 (m, 11H), 2.69-2.59 (m,1H), 2.25-2.22 (m, 1H), 1.82-1.60 (m, 3H), 1.40-1.33 (m, 3H), 1.05-0.96(m, 3H); MS (ESI) m/z 582.2 (M+H).

S25-11-26:

¹H NMR (400 MHz, CD₃OD) δ 7.23 (s, 1H), 4.61 (d, J=14.0 Hz, 1H), 4.45(d, J=13.6 Hz, 1H), 4.14 (s, 1H), 3.18-2.93 (m, 15H), 2.69-2.58 (m, 1H),2.27-2.23 (m, 1H), 1.67-1.58 (m, 1H); MS (ESI) m/z 540.1 (M+H).

S25-11-27:

¹H NMR (400 MHz, CD₃OD) δ 7.14 (s, 1H), 4.43 (d, J=14.4 Hz, 1H), 4.32(d, J=14.4 Hz, 1H), 4.14 (s, 1H), 3.20-2.91 (m, 9H), 2.84 (s, 3H),2.69-2.57 (m, 1H), 2.27-2.23 (m, 1H), 1.68-1.57 (m, 1H); MS (ESI) m/z526.0 (M+H).

S25-11-18:

¹H NMR (400 MHz, CD₃OD) δ 7.48-7.30 (m, 5H), 7.08 (s, 1H), 4.35-4.24 (m,2H), 4.15 (s, 1H), 3.45 (s, 2H), 3.21-2.96 (m, 9H), 2.69-2.53 (m, 1H),2.26-2.22 (m, 1H), 1.67-1.57 (m, 1H), 1.48 (d, J=2.4 Hz, 6H); MS (ESI)m/z 644.1 (M+H).

S25-11-29:

¹H NMR (400 MHz, CD₃OD) δ 7.23 (s, 1H), 4.71-4.61 (m, 1H), 4.41-4.24 (m,1H), 4.15 (s, 1H), 3.25-2.98 (m, 11H), 2.96-2.81 (m, 4H), 2.69-2.59 (m,1H), 2.26-2.20 (m, 3H), 2.10-2.01 (m, 1H), 1.99-1.90 (m, 1H), 1.69-1.59(m, 1H); MS (ESI) m/z 594.0 (M+H).

S25-11-30:

¹H NMR (400 MHz, CD₃OD) δ 7.22 (s, 1H), 4.80-4.75 (m, 1H), 4.42-4.24 (m,1H), 4.12 (s, 1H), 3.22-2.89 (m, 14H), 2.68-2.60 (m, 1H), 2.25-2.21 (m,1H), 1.69-1.62 (m, 1H), 1.27-1.10 (m, 1H), 0.83-0.80 (m, 2H), 0.50-0.47(m, 2H); MS (ESI) m/z 580.1 (M+H).

S25-11-31:

¹H NMR (400 MHz, CD₃OD) δ 7.21 (s, 1H), 4.62-4.43 (m, 2H), 4.11 (s, 1H),3.20-2.87 (m, 13H), 2.69-2.59 (m, 1H), 2.25-2.20 (m, 1H), 1.69-1.60 (m,1H), 1.41-1.33 (m, 3H), 1.28-1.10 (m, 1H), 0.83-0.75 (m, 2H), 0.46-0.38(m, 2H); MS (ESI) m/z 594.1 (M+H).

S25-11-32:

¹H NMR (400 MHz, CD₃OD) δ 7.23, 7.22 (s, 1H total), 4.63 (d, J=14.4 Hz,1H), 4.51-4.49 (m, 1H), 4.13 (s, 1H), 3.22-2.87 (m, 13H), 2.69-2.59 (m,1H), 2.26-2.23 (m, 1H), 1.71-1.60 (m, 3H), 1.41-1.33 (m, 3H), 099, 0.97(s, 9H total); MS (ESI) m/z 624.1 (M+H).

S25-11-33:

¹H NMR (400 MHz, CD₃OD) δ 7.50-7.28 (m, 5H), 7.07, 7.02 (s, 1H total),4.46-4.43 (m, 1H), 4.33-4.19 (m, 1H), 4.13 (s, 1H), 3.78-3.51 (m, 2H),3.22-2.86 (m, 9H), 2.66-2.57 (m, 4H), 2.24-2.21 (m, 1H), 1.66-1.47 (m,1H), 1.45 (s, 6H); MS (ESI) m/z 658.0 (M+H).

S25-11-34:

¹H NMR (400 MHz, CD₃OD) δ 7.51-7.24 (m, 5H), 7.09, 6.94 (s, 1H total),4.43-4.24 (m, 2H), 4.13 (s, 1H), 3.75-3.70 (m, 1H), 3.51-3.44 (m, 1H),3.21-2.94 (m, 11H), 2.67-2.58 (m, 1H), 2.24-2.21 (m, 1H), 1.60-1.52 (m,1H), 1.44 (t, J=7.2 Hz, 6H), 1.26-1.22 (m, 3H); MS (ESI) m/z 672.1(M+H).

S25-11-35:

¹H NMR (400 MHz, CD₃OD) δ 7.23 (s, 1H), 4.77-4.70 (m, 1H), 4.50, 38 (d,J=14.4 Hz, 1H, total), 4.13 (s, 1H), 3.89-3.68 (m, 3H), 3.52-3.40 (m,2H), 3.21-2.88 (m, 12H), 2.64-2.61 (m, 1H), 2.26-2.22 (m, 1H), 1.67-1.58(m, 1H), 1.20 (d, J=6.0 Hz, 6H); MS (ESI) m/z 612.4 (M+H).

S25-11-36:

¹H NMR (400 MHz, CD₃OD) δ 7.30, 7.26 (s, 1H total), 4.83-4.66 (m, 2H),4.13 (s, 1H), 3.84-3.80 (m, 2H), 3.70-3.67 (m, 1H), 3.53-3.40 (m, 4H),3.20-2.96 (m, 9H), 2.66-2.62 (m, 1H), 2.27-2.22 (m, 1H), 1.67-1.62 (m,1H), 1.42-1.35 (m, 3H), 1.29-1.21 (m, 6H); MS (ESI) m/z 626.3 (M+H).

S25-11-37:

¹H NMR (400 MHz, CD₃OD) δ 7.25 (s, 1H), 4.87-4.73 (m, 1H), 4.46-4.27 (m,1H), 4.16 (s, 1H), 3.30-2.79 (m, 14H), 2.69-2.56 (m, 1H), 2.28-2.25 (m,1H), 2.18-2.01 (m, 1H), 1.80-1.55 (m, 11H), 1.31-1.22 (m, 2H); MS (ESI)m/z 636.1 (M+H).

S25-11-38:

¹H NMR (400 MHz, CD₃OD) δ 7.24, 7.20 (s, 1H total), 4.61-4.40 (m, 2H),4.12 (s, 1H), 3.36-3.32 (m, 1H), 3.28-2.86 (m, 12H), 2.67-2.58 (m, 1H),2.25-2.21 (m, 1H), 2.16-2.09 (m, 1H), 1.89-1.41 (m, 12H), 1.40-1.14 (m,4H); MS (ESI) m/z 650.1 (M+H).

S25-11-39:

¹H NMR (400 MHz, CD₃OD) δ 7.31, 7.24 (s, 1H total), 4.76 (d, J=14.0 Hz,1H), 4.48-4.29 (m, 1H), 4.16 (s, 1H), 3.44-3.34 (m, 1H), 3.25-2.97 (m,9H), 2.84 (d, J=9.2 Hz, 3H), 2.66-2.59 (m, 1H), 2.30-2.12 (m, 2H),1.69-1.63 (m, 1H), 1.43, 1.35 (d, J=6.8 Hz, 3H total), 1.16-1.01 (m,6H); MS (ESI) m/z 596.6 (M+H).

S25-11-40:

¹H NMR (400 MHz, CD₃OD) δ 7.16 (s, 1H), 4.65 (t, J=15.2 Hz, 1H), 4.26(t, J=16.0 Hz, 1H), 4.07 (s, 1H), 3.35-3.30 (m, 1H), 3.18-2.82 (m, 9H),2.74 (s, 3H), 2.69-2.52 (m, 1H), 2.18-2.02 (m, 2H), 1.60-1.51 (m, 1H),1.32 (d, J=6.4 Hz, 3H), 1.01, 0.97 (d, J=6.4 Hz, 6H total); MS (ESI) m/z596.3 (M+H).

S25-11-41:

¹H NMR (400 MHz, CD₃OD) δ 7.25 (s, 1H), 4.70 (d, J=13.2 Hz, 1H),4.36-4.24 (m, 1H), 4.15 (s, 1H), 3.54-3.42 (m, 1H), 3.23-2.96 (m, 9H),2.79 (s, 3H), 2.69-2.59 (m, 1H), 2.28-2.22 (m, 1H), 1.97-1.92 (m, 1H),1.71-1.60 (m, 2H), 1.45-1.43 (m, 3H), 1.10-1.03 (m, 3H); MS (ESI) m/z582.0 (M+H).

S25-11-42:

¹H NMR (400 MHz, CD₃OD) δ 7.27, 7.25, 7.24 (s, 1H total), 4.75-4.63 (m,1H), 4.51-4.28 (m, 1H), 4.14 (s, 1H), 3.61-3.42 (m, 2H), 3.28-2.96 (m,10H), 2.67-2.58 (m, 1H), 2.27-2.23 (m, 1H), 1.97-1.88 (m, 1H), 1.81-1.60(m, 2H), 1.50-1.35 (m, 3H), 1.33-1.26 (m, 3H), 1.08-1.00 (m, 3H); MS(ESI) m/z 596.0 (M+H).

S25-11-43:

¹H NMR (400 MHz, CD₃OD) δ 7.07 (s, 1H), 4.39-4.32 (m, 1H), 4.24-4.20 (m,1H), 4.04 (s, 1H), 3.11-2.78 (m, 11H), 2.58-2.48 (m, 1H), 2.16-2.08 (m,1H), 1.68-1.50 (m, 8H), 1.35-1.08 (m, 4H), 0.98-0.81 (m, 2H); MS (ESI)m/z 622.3 (M+H).

S25-11-44:

¹H NMR (400 MHz, CD₃OD) δ 7.48-7.21 (m, 5H), 7.13 (s, 1H), 4.53-4.45 (m,1H), 4.37-4.30 (m, 1H), 4.12 (s, 1H), 3.46-3.36 (m, 2H), 3.19-2.89 (m,11H), 2.71-2.56 (m, 1H), 2.24-2.17 (m, 1H), 1.73-1.57 (m, 1H); MS (ESI)m/z 616.2 (M+H).

S25-11-45:

¹H NMR (400 MHz, CD₃OD) δ 7.23 (s, 1H), 4.42 (d, J=13.6 Hz, 2H), 4.13(s, 1H), 3.92-3.81 (m, 2H), 3.68-3.59 (m, 2H), 3.58-3.46 (m, 1H), 3.38(s, 3H), 3.20-2.96 (m, 9H), 2.65-2.54 (m, 1H), 2.38-2.12 (m, 3H),2.09-1.93 (m, 2H), 1.69-1.59 (m, 1H); MS (ESI) m/z 610.2 (M+H).

S25-11-46:

¹H NMR (400 MHz, CD₃OD) δ 7.14 (s, 1H), 4.90 (d, J=13.2 Hz, 1H), 4.20(d, J=13.2 Hz, 1H), 4.04 (s, 1H), 3.88-3.78 (m, 1H), 3.72-3.63 (m, 1H),3.61-3.56 (m, 1H), 3.43-3.28 (m, 5H), 3.19-2.82 (m, 9H), 2.64-2.50 (m,1H), 2.24-2.06 (m, 3H), 1.93-1.84 (m, 2H), 1.56-1.50 (m, 1H); MS (ESI)m/z 610.0 (M+H).

S25-11-47:

¹H NMR (400 MHz, CD₃OD) δ 7.28 (s, 1H), 4.58-4.44 (m, 2H), 4.12 (s, 1H),3.92-3.62 (m, 6H), 3.24-2.95 (m, 11H), 2.68-2.58 (m, 1H), 2.29-1.98 (m,5H), 1.68-1.59 (m, 1H); MS (ESI) m/z 609.0 (M+H).

S25-11-48:

¹H NMR (400 MHz, CD₃OD) δ 7.23 (s, 1H), 4.30 (d, J=14.0 Hz, 1H), 4.11(s, 1H), 3.69-3.62 (m, 1H), 3.53-3.41 (m, 1H), 3.40-3.32 (m, 2H),3.22-2.88 (m, 9H), 2.63-2.52 (m, 1H), 2.42-2.32 (m, 1H), 2.29-2.00 (m,3H), 1.82-1.77 (m, 1H), 1.71-1.58 (m, 1H), 1.43 (d, J=6.4 Hz, 3H); MS(ESI) m/z 579.9 (M+H).

S25-11-49:

¹H NMR (400 MHz, CD₃OD) δ 7.40 (s, 1H), 4.24 (d, J=13.6 Hz, 1H), 4.09(s, 1H), 4.01 (d, J=14.0 Hz, 1H), 3.59-3.43 (m, 1H), 3.22-2.94 (m, 11H),2.61-2.54 (m, 1H), 2.39-2.35 (m, 1H), 2.20-2.13 (m, 2H), 2.00-1.84 (m,2H), 1.67-1.57 (m, 1H); MS (ESI) m/z 634.1 (M+H).

S25-11-50:

¹H NMR (400 MHz, CD₃OD) δ 7.16 (s, 1H), 4.32-4.29 (m, 2H), 4.05 (s, 1H),3.11-2.86 (m, 11H), 2.60-2.52 (m, 1H), 2.17-2.14 (m, 1H), 1.59-1.23 (m,11H), 1.00 (s, 3H); MS (ESI) m/z 622.3 (M+H).

S25-11-51:

¹H NMR (400 MHz, CD₃OD) δ 7.18 (s, 1H), 4.49 (d, J=14.0 Hz, 1H), 4.31(d, J=13.6 Hz, 1H), 4.04 (s, 1H), 3.54-3.47 (m, 2H), 3.22 (s, 3H),3.12-2.86 (m, 13H), 2.60-2.48 (m, 1H), 2.16-2.13 (m, 1H), 1.89-1.86 (m,3H), 1.56-1.46 (m, 3H); MS (ESI) m/z 624.1 (M+H).

S25-11-52:

¹H NMR (400 MHz, CD₃OD) δ 7.30 (s, 1H), 4.60 (d, J=13.6 Hz, 1H), 4.42(d, J=14.0 Hz, 1H), 4.14 (s, 1H), 3.47-3.35 (m, 2H), 3.26-2.97 (m, 9H),2.78-2.60 (m, 3H), 2.27-2.23 (m, 1H), 2.02-1.94 (m, 2H), 1.89-1.82 (m,1H), 1.66 (ddd, J=13.6, 13.6, 13.6 Hz, 1H), 1.02-1.88 (m, 7H); MS (ESI)m/z 608.1 (M+H).

S25-11-53:

¹H NMR (400 MHz, CD₃OD) δ 7.12 (s, 1H), 4.71 (d, J=13.2 Hz, 1H), 4.07(d, J=13.2 Hz, 1H), 4.00 (s, 1H), 3.57-3.51 (m, 1H), 3.37-3.22 (m, 2H),3.08-2.78 (m, 9H), 2.54-2.45 (m, 1H), 2.29-2.24 (m, 1H), 2.12-1.89 (m,3H), 1.69-1.61 (m, 1H), 1.54-1.41 (m, 1H), 1.38 (d, J=6.0 Hz, 3H); MS(ESI) m/z 580.1 (M+H).

S25-11-54:

¹H NMR (400 MHz, CD₃OD) δ 7.05, 6.95, 6.87 (s, 1H total), 4.58-4.41 (m,1H), 4.41-4.32 (m, 1H), 4.21-4.14 (m, 2H), 3.99 (s, 1H), 3.93-3.72 (m,2H), 3.61-3.49 (m, 1H), 2.91-2.81 (m, 9H), 2.55-2.41 (m, 1H), 2.12-2.08(m, 1H), 1.54-1.44 (m, 1H), 1.22-1.04 (m, 3H); MS (ESI) m/z, 565.9(M+H).

S25-11-55:

¹H NMR (400 MHz, CD₃OD) δ 7.25 (s, 1H), 4.38 (s, 2H), 4.14 (s, 1H),3.37-3.34 (m, 1H), 3.25-2.96 (m, 9H), 2.66-2.58 (m, 1H), 2.27-2.16 (m,2H), 1.69-1.59 (m, 1H), 1.33 (d, J=6.8 Hz, 3H), 1.07 (d, J=6.8 Hz, 3H),1.00 (d, J=6.8 Hz, 3H); MS (ESI) m/z 582.1 (M+H).

S25-11-56:

¹H NMR (400 MHz, CD₃OD) δ 7.28 (s, 1H), 4.59 (d, J=14.4 Hz, 1H), 4.48(d, J=14.0H, 1H), 4.12 (s, 1H), 3.58-3.53 (m, 1H), 3.46-3.41 (m, 1H),3.35-3.33 (m, 1H), 3.28-2.94 (m, 10H), 2.60-2.54 (m, 1H), 2.25-2.20 (m,1H), 2.01-1.83 (m, 4H), 1.74 (s, 4H), 1.68-1.53 (m, 1H); MS (ESI) m/z594.0 (M+H).

S25-11-57:

¹H NMR (400 MHz, CD₃OD) δ 7.19 (s, 1H), 4.98 (t, J=8.8 Hz, 1H), 4.75 (t,J=8.8 Hz, 1H), 4.52-4.51 (m, 1H), 4.41-4.37 (m, 1H), 4.13 (s, 1H), 3.55(dt, J=31.6, 9.2 Hz, 2H), 3.21-3.08 (m, 9H), 2.64-2.55 (m, 1H),2.25-2.21 (m, 1H), 1.67-1.57 (m, 1H); MS (ESI) m/z 558.1 (M+H).

S25-11-58:

¹H NMR (400 MHz, CD₃OD) δ 7.24 (s, 1H), 4.42-4.38 (m, 1H), 4.27-4.21 (m,1H), 4.13 (s, 1H), 3.23-2.92 (m, 9H), 2.62-2.58 (m, 1H), 2.27-2.22 (m,1H), 1.69-1.62 (m, 1H), 1.47 (s, 9H); MS (ESI) m/z 568.0 (M+H).

S25-11-59:

¹H NMR (400 MHz, CD₃OD) δ 7.21 (s, 1H), 4.48-4.47 (m, 1H), 4.44-4.37 (m,1H), 4.13 (s, 1H), 4.13-4.07 (m, 3H), 3.90-3.85 (m, 1H), 3.76-3.73 (m,1H), 3.25-2.96 (m, 9H), 2.70-2.60 (m, 1H), 2.49-2.44 (m, 1H), 2.27-2.22(m, 1H), 2.14-2.11 (m, 1H), 1.69-1.61 (m, 1H); MS (ESI) m/z 582.1 (M+H).

S25-11-60:

¹H NMR (400 MHz, CD₃OD) δ 7.19 (s, 1H), 4.27 (d, J=13.6 Hz, 1H), 4.16(d, J=14.8 Hz, 1H), 4.12 (s, 1H), 3.24-2.94 (m, 9H), 2.67-2.56 (m, 1H),2.46-2.44 (m, 2H), 2.24-2.22 (m, 1H), 2.10-1.97 (m, 4H), 1.67-1.62 (m,4H); MS (ESI) m/z 579.9 (M+H).

S25-11-61:

¹H NMR (400 MHz, CD₃OD) δ 7.22 (s, 1H), 4.95-4.94 (m, 1H), 4.82-4.76 (m,1H), 4.11 (s, 1H), 3.69 (dt, J=30.8, 8.8 Hz, 2H), 3.20-2.94 (m, 14H),2.67-2.57 (m, 1H), 2.24-2.21 (m, 1H), 1.67-1.58 (m, 1H); MS (ESI) m/z572.0 (M+H).

S25-11-62:

¹H NMR (400 MHz, CD₃OD) δ 7.22 (s, 1H), 4.70 (d, J=13.6 Hz, 1H), 4.55(d, J=13.6 Hz, 1H), 4.11 (s, 1H), 3.68-3.63 (m, 2H), 3.48-3.41 (m, 2H),3.20-2.94 (m, 11H), 2.66-2.58 (m, 1H), 2.24-2.21 (m, 1H), 1.69-1.59 (m,1H), 1.40 (t, J=7.2 Hz, 3H); MS (ESI) m/z 586.0 (M+H).

S25-11-63:

¹H NMR (400 MHz, CD₃OD) δ 7.24 (s, 1H), 4.72-4.65 (m, 1H), 4.44-4.27 (m,1H), 4.13 (s, 1H), 3.03-2.94 (m, 11H), 2.85 (d, J=13.6 Hz, 3H),2.60-2.57 (m, 1H), 2.25-2.22 (m, 1H), 1.84-1.81 (m, 2H), 1.67-1.57 (m,1H), 1.02-1.00 (t, J=7.2 Hz, 3H); MS (ESI) m/z 568.0 (M+H).

S25-11-64:

¹H NMR (400 MHz, CD₃OD) δ 7.34 (s, 1H), 4.72 (d, J=13.6 Hz, 1H), 4.59(d, J=14.0 Hz, 1H), 4.15 (s, 1H), 3.85-3.79 (m, 2H), 3.04-2.95 (m, 9H),2.63-2.61 (m, 1H), 2.35-2.23 (m, 3H), 1.84-1.81 (m, 2H), 1.66-1.64 (m,1H), 1.36 (d, J=6.4 Hz, 3H), 1.22 (d, J=6.8 Hz, 3H); MS (ESI) m/z 594.1(M+H).

S25-11-65:

¹H NMR (400 MHz, CD₃OD) δ 7.28 (s, 1H), 4.73-4.70 (m, 1H), 4.58-4.48 (m,1H), 4.14 (s, 1H), 3.79-3.66 (m, 1H), 3.53-3.50 (m, 1H), 3.21-2.96 (m,11H), 2.69-2.58 (m, 1H), 2.28-2.23 (m, 1H), 2.05-1.95 (m, 2H), 1.66-1.62(m, 1H), 1.28, 1.22 (s, 6H total); MS (ESI) m/z 594.0 (M+H).

S25-11-66:

¹H NMR (400 MHz, CD₃OD) δ 7.23 (s, 1H), 4.75-4.68 (m, 1H), 4.44-4.41 (m,1H), 4.30-4.27 (m, 1H), 4.13 (s, 1H), 3.08-2.95 (m, 11H), 2.87 (d,J=14.0 Hz, 3H), 2.68-2.58 (m, 1H), 2.26-2.23 (m, 1H), 1.69-1.66 (m, 4H),1.00 (d, J=5.2 Hz, 6H); MS (ESI) m/z 596.0 (M+H).

S25-11-67:

¹H NMR (400 MHz, CD₃OD) δ 7.22 (s, 1H), 4.64-4.60 (m, 1H), 4.52-4.48 (m,1H), 4.13 (s, 1H), 3.41-3.35 (m, 2H), 3.19-2.96 (m, 11H), 2.64-2.52 (m,1H), 2.27-2.23 (m, 1H), 1.66-1.63 (m, 4H), 1.41-1.33 (m, 3H), 0.97 (d,J=5.2 Hz, 6H); MS (ESI) m/z 610.0 (M+H).

S25-11-68:

¹H NMR (400 MHz, CD₃OD) δ 7.35 (s, 1H), 4.58-4.55 (m, 1H), 4.45-4.42 (m,1H), 4.18 (s, 1H), 3.59-3.49 (m, 2H), 3.28-2.97 (m, 11H), 2.63-2.55 (m,1H), 2.29-2.26 (m, 1H), 1.94-1.82 (m, 5H), 1.66-1.58 (m, 2H); MS (ESI)m/z 580.0 (M+H).

S25-11-69:

¹H NMR (400 MHz, CD₃OD) δ 7.27 (s, 1H), 4.82-4.76 (m, 1H), 4.14 (s, 1H),4.05-4.02 (m, 1H), 3.60-3.47 (m, 2H), 3.11-2.95 (m, 9H), 2.60-2.55 (m,1H), 2.22-1.95 (m, 5H), 1.71-1.62 (m, 1H), 1.63 (s, 3H), 1.42 (s, 3H);MS (ESI) m/z 594.0 (M+H).

S25-11-70:

¹H NMR (400 MHz, CD₃OD) δ 7.24 (s, 1H), 4.80-4.77 (m, 1H), 4.44-4.25 (m,1H), 4.14 (s, 1H), 3.19-2.96 (m, 11H), 2.90 (d, J=7.6 Hz, 3H), 2.64-2.60(m, 1H), 2.27-2.22 (m, 2H), 1.69-1.60 (m, 1H), 1.09-1.01 (m, 6H); MS(ESI) m/z 582.0 (M+H).

S25-11-71:

¹H NMR (400 MHz, CD₃OD) δ 7.24 (s, 1H), 4.75-4.67 (m, 2H), 4.45-4.42 (m,1H), 4.31-4.27 (m, 1H), 4.14 (s, 1H), 3.18-2.96 (m, 9H), 2.87 (d, J=15.2Hz, 3H), 2.63-2.60 (m, 1H), 2.27-2.23 (m, 1H), 1.78-1.62 (m, 8H),1.31-1.25 (m, 4H), 1.04-1.02 (m, 2H); MS (ESI) m/z 636.1 (M+H).

S25-11-72:

¹H NMR (400 MHz, CD₃OD) δ 7.26 (s, 1H), 4.24-4.20 (m, 1H), 4.13 (s, 1H),3.53-3.43 (m, 4H), 3.09-2.95 (m, 9H), 2.69-2.62 (m, 1H), 2.48-2.41 (m,1H), 2.31-2.02 (m, 4H), 1.88-1.79 (m, 1H), 1.69-1.52 (m, 2H), 1.06 (t,J=7.2 Hz, 3H); MS (ESI) m/z 594.1 (M+H).

S25-11-73:

¹H NMR (400 MHz, CD₃OD) δ 7.25 (s, 1H), 4.75-4.72 (m, 1H), 4.36-4.33 (m,1H), 4.12 (s, 1H), 3.52-3.48 (m, 3H), 3.09-2.95 (m, 9H), 2.63-2.59 (m,1H), 2.48-2.41 (m, 1H), 2.25-2.16 (m, 2H), 2.05-1.95 (m, 2H), 1.88-1.79(m, 1H), 1.66-1.60 (m, 2H), 1.02 (t, J=7.2 Hz, 3H); MS (ESI) m/z 594.0(M+H).

S25-11-74:

¹H NMR (400 MHz, CD₃OD) δ 7.33-7.25 (m, 6H), 4.74-4.71 (m, 1H),4.52-4.35 (m, 1H), 4.12 (s, 1H), 3.52-3.48 (m, 2H), 3.14-2.92 (m, 14H),2.67-2.61 (m, 1H), 2.25-2.21 (m, 1H), 1.67-1.58 (m, 1H); MS (ESI) m/z630.1 (M+H).

S25-11-75:

¹H NMR (400 MHz, CD₃OD) δ 7.39 (s, 1H), 4.56-4.45 (m, 2H), 4.12 (s, 1H),3.74-3.60 (m, 6H), 3.04-2.95 (m, 11H), 2.81 (s, 3H), 2.61-2.57 (m, 1H),2.23-2.20 (m, 1H), 2.12-2.02 (m, 4H), 1.68-1.59 (m, 1H); MS (ESI) m/z623.1 (M+H).

S25-11-76:

¹H NMR (400 MHz, CD₃OD) δ 7.41 (s, 1H), 4.59-4.48 (m, 2H), 4.12 (s, 1H),3.74-3.58 (m, 6H), 3.20-2.95 (m, 13H), 2.61-2.57 (m, 1H), 2.24-2.11 (m,5H), 1.68-1.58 (m, 1H), 1.35 (t, J=7.2 Hz, 3H); MS (ESI) m/z 637.1(M+H).

S25-11-77:

¹H NMR (400 MHz, CD₃OD) δ 7.23 (s, 1H), 4.80-4.69 (m, 1H), 4.43-4.26 (m,1H), 4.13 (s, 1H), 3.41-3.35 (m, 2H), 3.03-2.94 (m, 9H), 2.85 (d, J=14.8Hz, 3H), 2.61-2.57 (m, 1H), 2.25-2.21 (m, 1H), 1.74-1.61 (m, 3H), 0.99,0.97 (s, 9H total); MS (ESI) m/z 610.1 (M+H).

S25-11-78:

¹H NMR (400 MHz, CD₃OD) δ 7.25 (s, 1H), 4.78-4.74 (m, 1H), 4.44-4.26 (m,1H), 4.14 (s, 1H), 3.30-2.96 (m, 11H), 2.90 (d, J=9.6 Hz, 3H) 2.63-2.59(m, 1H), 2.40-2.37 (m, 1H), 2.27-2.23 (m, 1H), 1.97-1.91 (m, 2H),1.73-1.63 (m, 5H), 1.33-1.27 (m, 2H); MS (ESI) m/z 608.2 (M+H).

S25-11-79:

¹H NMR (400 MHz, CD₃OD) δ 7.24, 7.21 (s, 1H total), 4.69-4.42 (m, 2H),4.13 (s, 1H), 3.09-2.96 (m, 13H), 2.65-2.58 (m, 1H), 2.31-2.22 (m, 2H),1.68-1.52 (m, 7H), 1.40 (t, J=7.2 Hz, 3H), 1.28-1.21 (m, 2H); MS (ESI)m/z 622.4 (M+H).

S25-11-80:

¹H NMR (400 MHz, CD₃OD) δ 7.16, 7.14 (s, 1H total), 4.69-4.66 (m, 1H),4.35-4.17 (m, 1H), 4.05 (s, 1H), 3.20-2.87 (m, 11H), 2.80 (d, J=11.2 Hz,3 H), 2.56-2.49 (m, 1H), 2.17-2.14 (m, 1H), 1.78-1.56 (m, 7H), 1.27-1.00(m, 3H), 0.97-0.92 (m, 2H); MS (ESI) m/z 622.0 (M+H.

S25-11-81:

¹H NMR (400 MHz, CD₃OD) δ 7.23, 7.19 (s, 1H total), 4.65-4.40 (m, 2H),4.11 (s, 1H), 3.10-2.86 (m, 13H), 2.67-2.64 (m, 1H), 2.24-2.21 (m, 1H),1.82-1.64 (m, 7H), 1.39-1.18 (m, 6H), 1.01-0.98 (m, 2H); MS (ESI) m/z636.1 (M+H).

S25-11-82:

¹H NMR (400 MHz, CD₃OD) δ 7.26 (s, 1H), 4.58 (d, J=14.4 Hz, 1H), 4.45(d, J=14.4 Hz, 1H), 4.13 (s, 1H), 3.47-3.41 (m, 2H), 3.12-2.95 (m, 11H),2.69-2.58 (m, 1H), 2.26-2.22 (m, 1H), 1.78-1.62 (m, 5H), 1.12 (s, 3H),1.04 (s, 3H), MS (ESI) m n 608.3 (M+H).

S25-11-83:

¹H NMR (400 MHz, CD₃OD) δ 7.35, 7.26 (s, 1H total), 4.70-4.67 (m, 1H),4.54-4.34 (m, 1H), 4.15 (s, 1H), 3.42-3.38 (m, 1H), 3.21-2.86 (m, 13H),2.69-2.63 (m, 1H), 2.24-2.17 (m, 2H), 2.02-1.69 (m, 8H), 0.93, 0.84 (t,J=6.8 Hz, 3H total); MS (ESI) m/z 622.4 (M+H).

S25-11-84:

¹H NMR (400 MHz, CD₃OD) δ 7.37, 7.36, 7.31, 7.30 (s, 1H total),4.65-4.50 (m, 2H), 4.15 (s, 1H), 3.48-3.38 (m, 2H), 3.25-2.96 (m, 11H),2.68-2.53 (m, 1H), 2.27-2.24 (m, 1H), 2.05-1.63 (m, 8H), 1.47-1.44 (m,3H), 0.91, 0.79 (t, J=7.2 Hz, 3H total); MS (ESI) m/z 636.6 (M+H).

S25-11-85:

¹H NMR (400 MHz, CD₃OD) δ 7.23 (s, 1H), 4.71-4.68 (m, 1H), 4.31-4.22 (m,1H), 4.12 (s, 1H), 3.81-3.73 (m, 1H), 3.18-2.95 (m, 9H), 2.77 (s, 3H),2.67-2.59 (m, 1H), 2.25-2.21 (m, 1H), 1.68-1.59 (m, 1H), 1.42 (d, J=5.6Hz, 6H); MS (ESI) m/z 568.0 (M+H).

S25-11-86:

¹H NMR (400 MHz, CD₃OD) δ 7.26, 7.24 (s, 1H total), 4.74-4.62 (m, 1H),4.48-4.28 (m, 1H), 4.14 (s, 1H), 3.88-3.72 (m, 1H), 3.28-2.91 (m, 11H),2.62-2.59 (m, 1H), 2.26-2.23 (m, 1H), 1.66-1.63 (m, 1H), 1.51-1.39 (m,6H), 1.33, 1.27 (t, J=7.2 Hz, 3H total); MS (ESI) m/z 582.1 (M+H).

S25-11-87:

¹H NMR (400 MHz, CD₃OD) δ 7.26 (s, 1H), 4.67-4.59 (m, 1H), 4.31-4.28 (m,0.5H), 4.19-4.15 (m, 0.5H), 4.14 (s, 1H), 3.95-3.91 (m, 1H), 3.18-2.96(m, 9H), 2.73 (d, J=7.2 Hz, 3H), 2.69-2.59 (m, 1H), 2.41-2.38 (m, 3H),2.27-2.24 (m, 2H), 1.91-1.81 (m, 2H), 1.69-1.59 (m, 1H); MS (ESI) m/z580.0 (M+H).

S25-11-88:

¹H NMR (400 MHz, CD₃OD) δ 7.29 (s, 1H), 4.32-4.21 (m, 3H), 4.18-4.16 (m,1H), 4.15 (s, 1H), 3.83-3.72 (m, 2H), 3.11-2.96 (m, 10H), 2.82 (s, 3H),2.65-2.61 (m, 1H), 2.46-2.35 (m, 2H), 2.26-2.23 (m, 1H), 1.69-1.63 (m,1H); MS (ESI) m/z 596.0 (M+H).

S25-11-89:

¹H NMR (400 MHz, CD₃OD) δ 7.30-7.22 (m, 5H), 4.76-4.45 (m, 4H), 4.14 (s,1H), 3.51-3.45 (m, 4H), 3.19-2.96 (m, 10H), 2.65-2.61 (m, 1H), 2.26-2.23(m, 1H), 1.67-1.60 (m, 1H), 1.40-1.35 (m, 3H); MS (ESI) m/z 656.0 (M+H).

S25-11-90:

¹H NMR (400 MHz, CD₃OD) δ 7.22 (s, 1H), 4.72-4.61 (m, 1H), 4.51-4.42 (m,1H), 4.33-4.10 (m, 4H), 3.90-3.60 (m, 3H), 3.12-2.89 (m, 10H), 2.69-2.58(m, 1H), 2.41-2.20 (m, 3H), 1.65-1.62 (m, 1H), 1.37-1.27 (m, 3H); MS(ESI) m/z 610.2 (M+H).

S25-11-91:

¹H NMR (400 MHz, CD₃OD) δ 7.24, 7.22 (s, 1H total), 4.78-4.74 (m, 1H),4.31-4.20 (m, 1H), 4.13 (s, 1H), 3.47-3.37 (m, 1H), 3.21-2.92 (m, 9H),2.79 (d, J=5.2 Hz, 3H), 2.66-2.59 (m, 1H), 2.25-2.22 (m, 1H), 2.12-2.09(m, 2H), 2.01-1.92 (m, 2H), 1.74-1.60 (m, 4H), 1.46-1.40 (m, 2H),1.32-1.22 (m, 1H); MS (ESI) m/z 608.3 (M+H).

S25-11-92:

¹H NMR (400 MHz, CD₃OD) δ 7.25, 7.24 (s, 1H total), 4.83-4.82 (m, 1H),4.22-4.10 (m, 1H), 4.12 (s, 1H), 3.20-2.90 (m, 9H), 2.70 (d, J=10.8 Hz,3H), 2.65-2.57 (m, 1H), 2.24-2.21 (m, 1H), 1.67-1.61 (m, 1H), 1.53 (s,9H); MS (ESI) m/z 582.1 (M+H).

S25-11-93:

¹H NMR (400 MHz, CD₃OD) δ 7.35, 7.30 (s, 1H total), 4.76-4.73 (m, 1H),4.49-4.38 (m, 1H), 4.11 (s, 1H), 3.53-3.47 (m, 1H), 3.18-2.91 (m, 10H),2.66-2.59 (m, 1H), 2.23-2.20 (m, 1H), 1.67-1.61 (m, 1H), 1.56, 1.53 (s,9H total), 1.13, 1.03 (t, J=7.2 Hz, 3H total); MS (ESI) m/z 596.1 (M+H).

S25-11-94:

¹H NMR (400 MHz, CD₃OD) δ 7.23, 7.22 (s, 1H total), 4.82-4.73 (m, 1H),4.26-4.14 (m, 1H), 4.11 (s, 1H), 3.22-2.92 (m, 9H), 2.71, 2.68 (s, 3Htotal), 2.65-2.58 (m, 1H), 2.24-2.21 (m, 1H), 1.95-1.87 (m, 2H),1.67-1.58 (m, 1H), 1.50, 1.48 (s, 6H total), 1.06 (t, J=7.2 Hz, 3H); MS(ESI) m/z 596.0 (M+H).

S25-11-95:

¹H NMR (400 MHz, CD₃OD) δ 7.37, 7.32 (s, 1H total), 4.79-4.75 (m, 1H),4.52-4.41 (m, 1H), 4.12 (s, 1H), 3.58-3.52 (m, 1H), 3.20-2.92 (m, 10H),2.68-2.60 (m, 1H), 2.25-2.21 (m, 1H), 1.96-1.90 (m, 2H), 1.69-1.59 (m,1H), 1.53-1.50 (m, 6H), 1.07-1.01 (m, 6H); MS (ESI) m/z 610.1 (M+H).

S25-11-96:

¹H NMR (400 MHz, CD₃OD) δ 7.26, 7.24 (s, 1H total), 4.79-4.73 (m, 1H),4.26-4.15 (m, 1H), 4.13 (s, 1H), 3.21-2.92 (m, 9H), 2.70, 2.68 (s, 3Htotal), 2.70-2.58 (m, 1H), 2.25-2.21 (m, 1H), 1.96-1.93 (m, 1H),1.82-1.79 (m, 1H), 1.67-1.63 (m, 7H), 1.13 (s, 9H); MS (ESI) m/z 638.1(M+H).

S25-11-97:

¹H NMR (400 MHz, CD₃OD) δ 7.40, 7.35 (s, 1H total), 4.78-4.75 (m, 1H),4.52-4.41 (m, 1H), 4.12 (s, 1H), 3.63-3.55 (m, 1H), 3.07-2.95 (m, 10H),2.67-2.60 (m, 1H), 2.25-2.22 (m, 1H), 1.94-1.86 (m, 2H), 1.82-1.79 (m,7H), 1.13, 1.11 (s, 9H total), 0.98 (t, J=7.2 Hz, 3H); MS (ESI) m/z652.1 (M+H).

S25-11-98:

¹H NMR (400 MHz, CD₃OD) δ 7.28 (s, 1H), 4.80-4.76 (m, 1H), 4.41-4.30 (m,1H), 4.15 (s, 1H), 3.21-2.95 (m, 10H), 2.84, 2.89 (s, 3H total),2.67-2.58 (m, 1H), 2.28-2.25 (m, 1H), 1.69-1.60 (m, 1H), 1.54-1.49 (m,3H), 1.23-1.20 (m, 1H), 0.85-0.71 (m, 3H), 0.52-0.41 (m, 1H); MS (ESI)m/z 594.2 (M+H).

S25-11-99:

¹H NMR (400 MHz, CD₃OD) δ 7.27, 7.26 (s, 1H total), 4.97-4.94 (m, 1H),4.80-4.44 (m, 1H), 4.62-4.58 (m, 0.4H), 4.32-4.29 (m, 0.6H), 4.14 (s,1H), 3.21-2.92 (m, 11H), 2.68-2.61 (m, 1H), 2.27-2.23 (m, 1H), 1.70-1.60(m, 1H), 1.51-1.47 (m, 3H), 1.37, 1.24 (t, J=7.2 Hz, 3H total),1.35-1.31 (m, 1H), 0.85-0.82 (m, 2H), 0.64-0.39 (m, 2H); MS (ESI) m/z608.2 (M+H).

S25-11-100:

¹H NMR (400 MHz, CD₃OD) δ 7.30 (s, 1H), 4.77-4.73 (m, 2H), 4.13 (s, 1H),3.24-2.92 (m, 12H), 2.65-2.57 (m, 1H), 2.25-2.22 (m, 1H), 1.64-1.61 (m,2H), 1.19-1.14 (m, 2H), 0.92-0.81 (m, 2H), 0.77-0.75 (m, 2H), 0.40-0.32(m, 2H); MS (ESI) m/z 606.0 (M+H).

S25-11-101:

¹H NMR (400 MHz, CD₃OD) δ 7.30 (s, 1H), 4.82-4.75 (m, 2H), 4.12 (s, 1H),3.70-3.62 (m, 1H), 3.21-2.92 (m, 10H), 2.65-2.57 (m, 1H), 2.24-2.21 (m,1H), 1.64-1.62 (m, 2H), 1.41-1.37 (m, 4H), 1.00-0.68 (m, 5H), 0.51-0.24(m, 2H); MS (ESI) m/z 620.1 (M+H).

S25-11-102:

¹H NMR (400 MHz, CD₃OD) δ 7.26, 7.21 (s, 1H total), 4.75-4.72 (m, 1H),4.34-4.28 (m, 1H), 4.13 (s, 1H), 3.71-3.62 (m, 1H), 3.11-2.92 (m, 9H),2.85-2.78 (m, 3H), 2.65-2.58 (m, 1H), 2.39-2.35 (m, 1H), 2.25-2.22 (m,1H), 2.18-2.12 (m, 1H), 1.73-1.53 (m, 8H), 1.43-1.28 (m, 1H); MS (ESI)m/z 620.0 (M+H).

S25-11-103:

¹H NMR (400 MHz, CD₃OD) δ 7.30, 7.28, 7.25 (s, 1H total), 4.79-4.75 (m,1H), 4.66-4.48 (m, 1H), 4.13 (s, 1H), 3.82-3.78 (m, 1H), 3.22-2.92 (m,11H), 2.69-2.60 (m, 2H), 2.40-2.38 (m, 1H), 2.26-2.23 (m, 1H), 2.13-2.07(m, 1H), 1.68-1.41 (m, 8H), 1.29, 1.23 (t, J=7.2 Hz, 3H total); MS (ESI)m/z 634.1 (M+H).

S25-11-104:

¹H NMR (400 MHz, CD₃OD) δ 7.37, 7.30 (s, 1H total), 4.79-4.76 (m, 1H),4.60-4.42 (m, 1H), 4.15 (s, 1H), 3.29-2.98 (m, 14H), 2.64-2.60 (m, 1H),2.28-2.25 (m, 1H), 1.72-1.65 (m, 1H), 1.15, 1.07 (s, 9H total); MS (ESI)m/z 596.2 (M+H).

S25-11-105:

¹H NMR (400 MHz, CD₃OD) δ 7.38, 7.31 (s, 1H total), 4.69-4.62 (m, 2H),4.14 (s, 1H), 3.52-3.41 (m, 2H), 3.28-2.88 (m, 11H), 2.70-2.61 (m, 1H),2.28-2.24 (m, 1H), 1.71-1.61 (m, 1H), 1.51-1.44 (m, 3H), 1.09, 0.99 (s,9H total); MS (ESI) m/z 610.0 (M+H).

S25-11-106:

¹H NMR (400 MHz, CD₃OD) δ 7.42 (s, 1H), 4.76-4.72 (m, 1H), 4.57-4.53 (m,1H), 4.13 (s, 1H), 3.20-2.92 (m, 13H), 2.61-2.58 (m, 1H), 2.26-2.23 (m,1H), 1.69-1.60 (m, 1H), 1.39, 1.38 (s, 3H total), 0.97 (s, 9H); MS (ESI)m/z 610.0 (M+H).

S25-11-106:

¹H NMR (400 MHz, CD₃OD) δ 7.29 (s, 1H), 4.97-4.94 (m, 1H), 4.43-4.28 (m,1H), 4.14 (s, 1H), 3.94-3.63 (m, 1H), 3.21-2.98 (m, 9H), 2.85, 2.74 (s,3H total), 2.67-2.59 (m, 1H), 2.50-2.42 (m, 1H), 2.27-2.24 (m, 1H),1.94-1.93 (m, 1H), 1.82-1.52 (m, 6H), 1.25, 1.18 (s, 3H total),0.98-0.93 (m, 6H); MS (ESI) m/z 662.0

S25-11-107:

¹H NMR (400 MHz, CD₃OD) δ 7.38 (s, 1H), 4.95-4.92 (m, 1H), 4.43-4.40 (m,1H), 4.14 (s, 1H), 3.79-3.76 (m, 1H), 3.21-2.91 (m, 11H), 2.69-2.62 (m,1H), 2.47-2.41 (m, 1H), 2.27-2.24 (m, 1H), 1.82-1.58 (m, 6H), 1.47-1.44(m, 1H), 1.26-1.21 (m, 6H), 1.00-0.98 (m, 5H), 0.93 (s, 1H); MS (ESI)m/z 676.1 (M+H).

S25-11-108:

¹H NMR (400 MHz, CD₃OD) δ 7.28, 7.25 (s, 1H total), 4.76-4.72 (m, 1H),4.50-4.32 (m, 1H), 4.14 (s, 1H), 3.28-2.95 (m, 11H), 2.91 (s, 3H),2.66-2.60 (m, 2H), 2.46-2.44 (m, 1H), 2.27-2.15 (m, 2H), 2.02-1.94 (m,5H), 1.66-1.60 (m, 1H), 1.22 (s, 3H), 1.08-1.06 (m, 1H), 0.94, 0.91 (s,3H total); MS (ESI) m/z 662.1 (M+H).

S25-11-109

¹H NMR (400 MHz, CD₃OD) δ 7.28, 7.26, 7.25 (s, 1H total), 4.67-4.61 (m,1H), 4.57-4.50 (m, 1H), 4.42-4.36 (m, 1H), 4.14 (s, 1H), 3.38-3.37 (m,1H), 3.28-2.88 (m, 11H), 2.67-2.45 (m, 3H), 2.28-2.05 (m, 2H), 2.00-1.91(m, 5H), 1.67-1.61 (m, 1H), 1.41 (t, J=5.6 Hz, 3H), 1.26-1.17 (m, 3H),1.06-1.04 (m, 2H), 0.88-0.83 (m, 2H); MS (ESI) m/z 676.1 (M+H).

S25-11-110:

¹H NMR (400 MHz, CD₃OD) δ 7.25 (s, 1H), 4.72-4.58 (m, 2H), 4.12 (s, 1H),3.05-2.96 (m, 13H), 2.70-2.59 (m, 1H), 2.25-2.22 (m, 1H), 1.70-1.61 (m,1H), 1.01-0.93 (m, 4H); MS (ESI) m/z 566.0 (M+H).

S25-11-111:

¹H NMR (400 MHz, CD₃OD) δ 7.27 (s, 1H), 4.72-4.64 (m, 2H), 4.14 (s, 1H),3.50-3.44 (m, 1H), 3.21-2.82 (m, 11H), 2.62-2.59 (m, 1H), 2.26-2.23 (m,1H), 1.70-1.60 (m, 1H), 1.51-1.43 (m, 3H), 1.10-0.80 (m, 3H), 0.70-0.32(m, 1H); MS (ESI) m/z 580.0 (M+H).

S25-11-112:

¹H NMR (400 MHz, CD₃OD) δ 7.28 (s, 1H), 4.76-4.67 (m, 2H), 4.12 (s, 1H),3.45-3.39 (m, 1H), 3.18-2.91 (m, 11H), 2.67-2.57 (m, 1H), 2.25-2.22 (m,1H), 1.68-1.58 (m, 1H), 1.31-1.25 (m, 2H), 1.08-0.92 (m, 1H), 0.84-0.82(m, 3H), 0.52-0.47 (m, 3H); MS (ESI) m/z 606.0 (M+H).

S25-11-113:

¹H NMR (400 MHz, CD₃OD) δ 7.21 (s, 1H), 4.63-4.59 (m, 1H), 4.49-4.46 (m,1H), 4.12 (s, 1H), 3.24-2.92 (m, 13H), 2.68-2.58 (m, 1H), 2.25-2.22 (m,1H), 1.74-1.63 (m, 8H), 1.43-1.38 (m, 1H), 1.36-1.24 (m, 6H), 1.02-0.97(m, 2H); MS (ESI) m/z 650.2 (M+H).

S25-11-114:

¹H NMR (400 MHz, CD₃OD) δ 7.24 (s, 1H), 4.82-4.58 (m, 2H), 4.13 (s, 1H),3.28-2.92 (m, 13H), 2.68-2.59 (m, 1H), 2.26-2.23 (m, 1H), 1.73-1.63 (m,8H), 1.28-1.17 (m, 5H), 1.02-0.97 (m, 2H), 0.81-0.77 (m, 2H), 0.47-0.41(m, 2H); MS (ESI) m/z 676.2 (M+H).

S25-11-115:

¹H NMR (400 MHz, CD₃OD) δ 7.25 (s, 1H), 4.97 (m, 1H), 4.64 (m, 1H),4.68-4.62 (m, 1H), 4.12 (s, 1H), 3.85-3.58 (m, 1H), 3.25-2.90 (m, 13H),2.64-2.57 (m, 1H), 2.24-2.21 (m, 1H), 1.68-1.58 (m, 1H), 1.22-1.15 (m,1H), 0.81-0.79 (m, 2H), 0.48-0.44 (m, 2H); MS (ESI) m/z 612.1 (M+H).

S25-11-116:

¹H NMR (400 MHz, CD₃OD) δ 7.28, 7.24 (s, 1H total), 4.78-4.74 (m, 1H),4.65-4.62 (m, 1H), 4.08 (s, 1H), 3.78-3.72 (m, 2H), 3.66-3.63 (m, 1H),3.52-3.43 (m, 1H), 3.20-2.82 (m, 12H), 2.64-2.55 (m, 1H), 2.20-2.17 (m,1H), 1.65-1.56 (m, 1H), 1.17-1.16 (m, 7H), 0.76-0.72 (m, 2H), 1.43-0.39(m, 2H); MS (ESI) m/z 652.1 (M+H).

S25-11-117:

¹H NMR (400 MHz, CD₃OD) δ 7.21 (s, 1H), 4.81-4.77 (m, 1H), 4.62-4.58 (m,1H), 4.10 (s, 1H), 3.36-3.33 (m, 1H), 3.22-2.91 (m, 12H), 2.64-2.55 (m,1H), 2.21-2.18 (m, 1H), 1.65-1.55 (m, 1H), 1.17-1.11 (m, 2H), 0.76-0.73(m, 4H), 0.43-0.32 (m, 4H); MS (ESI) m/z 620.0 (M+H).

S25-11-118:

¹H NMR (400 MHz, CD₃OD) δ 7.18 (s, 1H), 4.75-4.72 (m, 0.5H), 4.55 (m,1H), 4.46-4.42 (m, 0.5H), 4.10 (s, 1H), 3.42-3.40 (m, 1H), 3.12-2.85 (m,13H), 2.65-2.55 (m, 1H), 2.21-2.10 (m, 4H), 1.99-1.97 (m, 1H), 1.91-1.81(m, 4H), 1.65-1.56 (m, 1H), 1.15-1.09 (m, 1H), 0.77-0.73 (m, 2H),0.42-0.36 (m, 2H); MS (ESI) m/z 634.0 (M+H).

S25-11-119:

¹H NMR (400 MHz, CD₃OD) δ 7.42, 7.38 (s, 1H total), 4.82-4.71 (m, 2H),4.13 (s, 1H), 3.48-3.38 (m, 2H), 3.28-2.83 (m, 11H), 2.68-2.60 (m, 1H),2.26-2.23 (m, 1H), 1.69-1.60 (m, 1H), 1.34-1.28 (m, 1H), 1.05, 0.95 (s,9H total), 0.88-0.84 (m, 2H), 0.53-0.48 (m, 2H); MS (ESI) m/z 636.1(M+H).

S25-11-120:

¹H NMR (400 MHz, CD₃OD) δ 7.43, 7.31 (s, 1H total), 4.89-4.82 (m, 0.5H),4.71-4.67 (m, 1H), 4.32-4.29 (m, 0.5H), 4.14 (s, 1H), 3.50-3.47 (m, 2H),3.22-2.96 (m, 10H), 2.67-2.64 (m, 1H), 2.27-2.23 (m, 2H), 1.66-1.60 (m,1H), 1.44-1.28 (m, 6H), 1.15-0.99 (m, 6H); MS (ESI) m/z 610.0 (M+H).

S25-11-121:

¹H NMR (400 MHz, CD₃OD) δ 7.27 (s, 1H), 4.62-4.38 (m, 2H), 4.14 (s, 1H),4.01 (s, 1H), 3.25-2.88 (m, 11H), 2.69-2.57 (m, 1H), 2.45-2.33 (m, 2H),2.27-2.05 (m, 2H), 2.02-1.71 (m, 3H), 1.69-1.58 (m, 1H), 1.48-1.37 (m,3H); MS (ESI) m/z 594.2 (M+H).

S25-11-122:

¹H NMR (400 MHz, CD₃OD) δ 7.28 (s, 1H), 4.82-4.75 (m, 1H), 4.50-4.31 (m,1H), 4.15 (s, 1H), 3.99-3.75 (m, 3H), 3.52-3.35 (m, 3H), 3.25-2.82 (m,13H), 2.69-2.63 (m, 1H), 2.27-2.24 (m, 2H), 1.70-1.60 (m, 2H); MS (ESI)m/z 610.2 (M+H).

S25-11-123:

¹H NMR (400 MHz, CD₃OD) δ 7.24 (s, 1H), 4.73-4.49 (m, 2H), 4.13 (s, 1H),3.95-3.75 (m, 3H), 3.48-3.30 (m, 3H), 3.25-2.70 (m, 12H), 2.69-2.60 (m,1H), 2.26-2.23 (m, 2H), 1.72-1.60 (m, 2H), 1.40 (t, J=7.2 Hz, 3H); MS(ESI) m/z 624.2 (M+H).

S25-11-124:

¹H NMR (400 MHz, CD₃OD) δ 7.31-7.21 (m, 5H), 4.40-4.36 (m, 2H), 4.14 (s,1H), 3.60-3.33 (m, 5H), 3.25-2.82 (m, 9H), 2.79 (s, 3H), 2.68-2.61 (m,1H), 2.26-2.23 (m, 1H), 1.69-1.59 (m, 1H); MS (ESI) m/z 642.1 (M+H).

S25-11-125:

¹H NMR (400 MHz, CD₃OD) δ 7.26 (s, 1H), 4.81-4.71 (m, 1H), 4.44-4.26 (m,1H), 4.15 (s, 1H), 3.84-3.82 (m, 1H), 3.21-2.87 (m, 9H), 2.78 (s, 3H),2.69-2.55 (m, 1H), 2.35-2.17 (m, 3H), 1.95-1.73 (m, 4H), 1.69-1.59 (m,3H); MS (ESI) m/z 594.1 (M+H).

S25-11-126:

¹H NMR (400 MHz, CD₃OD) δ 7.26, 7.24 (s, 1H total), 4.75-4.71 (m, 0.6H),4.61-4.59 (m, 1H), 4.52-4.48 (m, 0.5H), 4.14 (s, 1H), 3.89-3.82 (m, 1H),3.25-2.95 (m, 11H), 2.65-2.62 (m, 1H), 2.26-2.14 (m, 3H), 1.95-1.84 (m,4H), 1.72-1.62 (m, 3H), 1.35, 1.28 (t, J=7.2 Hz, 3H total); MS (ESI) m/z608.2 (M+H).

S25-11-127:

¹H NMR (400 MHz, CD₃OD) δ 7.21, 7.20 (s, 1H total), 4.80-4.68 (m, 1H),4.44-4.40 (m, 0.5H), 4.28-4.25 (m, 0.5H), 4.11 (s, 1H), 3.59-3.42 (m,2H), 3.24-2.85 (m, 10H), 2.67-2.56 (m, 1H), 2.23-1.90 (m, 5H), 1.83-1.58(m, 4H), 1.45-1.24 (m, 6H); MS (ESI) m/z 622.3 (M+H).

S25-11-128:

¹H NMR (400 MHz, CD₃OD) δ 7.33, 7.24 (s, 1H total), 5.03-4.96 (m, 2H),4.14-4.10 (m, 3H), 3.87-3.62 (m, 2H), 3.48-3.38 (m, 1H), 3.25-2.89 (m,9H), 2.70-2.63 (m, 1H), 2.27-2.24 (m, 1H), 1.71-1.55 (m, 3H), 1.35-1.19(m, 4H), 0.98 (s, 6H); MS (ESI) m/z 640.0 (M+H).

S25-11-129:

¹H NMR (400 MHz, CD₃OD) δ 7.69-7.49 (m, 5H), 7.13 (s, 1H), 4.49-4.32 (m,4H), 4.13 (s, 1H), 3.23-2.88 (m, 9H), 2.70-2.56 (m, 1H), 2.29-2.22 (m,1H), 1.68-1.59 (m, 1H); MS (ESI) m/z 602.1 (M+H).

S25-11-130:

¹H NMR (400 MHz, CD₃OD) δ 7.15 (s, 1H), 4.53 (d, J=14.0 Hz, 1H), 4.43(d, J=12.4 Hz, 1H), 4.12 (s, 1H), 3.23-2.86 (m, 10H), 2.67-2.55 (m, 1H),2.25-2.21 (m, 1H), 1.67-1.57 (m, 1H), 0.96-0.95 (m, 4H); MS (ESI) m/z552.1 (M+H).

S25-11-131:

¹H NMR (400 MHz, CD₃OD) δ 7.53-7.49 (m, 5H), 7.31, 7.16 (s, 1H total),4.63-4.23 (m, 4H), 4.13 (s, 1H), 3.22-2.89 (m, 11H), 2.70-2.56 (m, 1H),2.26-2.22 (m, 1H), 1.69-1.59 (m, 1H), 1.48 (t, J=7.2 Hz, 3H); MS (ESI)m/z 630.1 (M+H).

S25-11-132:

¹H NMR (400 MHz, CD₃OD) δ 7.67-7.46 (m, 5H), 7.23, 7.18 (s, 1H total),4.63-4.39 (m, 4H), 4.12 (s, 1H), 3.22-2.81 (m, 11H), 2.68-2.53 (m, 1H),2.23-2.20 (m, 1H), 1.66-1.58 (m, 1H), 1.36-1.31 (m, 1H), 0.85-0.78 (m,2H), 0.47-0.42 (m, 2H); MS (ESI) m/z 656.2 (M+H).

S25-11-133:

¹H NMR (400 MHz, CD₃OD) δ 7.55-7.52 (m, 5H), 7.14, 6.99 (s, 1H total),4.62-4.55 (m, 0.4H), 4.40-4.25 (m, 1H), 4.13-3.98 (m, 1.5H), 3.22-2.88(m, 10H), 2.71-2.56 (m, 1H), 2.24-2.21 (m, 1H), 1.80-1.1.78 (m, 3H),1.66-1.59 (m, 1H); MS (ESI) m/z 616.2 (M+H).

S25-11-134:

¹H NMR (400 MHz, CD₃OD) δ 7.21-6.99 (m, 5H), 6.89, 6.79 (s, 1H total),4.72-4.62 (m, 1H), 3.86 (s, 1H), 3.62-3.52 (m, 1H), 3.32-3.10 (m, 2H),3.00-2.55 (m, 11H), 2.40-2.39 (m, 1H), 2.02-1.95 (m, 1H), 1.42-1.33 (m,1H), 1.29-1.09 (m, 6H), 0.93-0.80 (m, 1H), 0.52-0.42 (m, 2H), 0.10-0.01(m, 2H); MS (ESI) m/z 698.1 (M+H).

S25-11-135:

¹H NMR (400 MHz, CD₃OD) δ 7.48 (s, 1H), 4.83-4.62 (m, 2H), 4.13 (s, 1H),3.85-3.63 (m, 6H), 3.23-2.87 (m, 13H), 2.68-2.58 (m, 1H), 2.28-2.00 (m,5H), 1.68-1.59 (m, 1H), 1.29-1.18 (m, 1H), 0.86-0.78 (m, 2H), 0.52-0.42(m, 2H); MS (ESI) m/z 663.3 (M+H).

S25-11-136:

¹H NMR (400 MHz, CD₃OD) δ 7.32, 7.24, 7.23 (s, 1H total), 4.78-4.50 (m,2H), 4.12, 3.87 (s, 1H total), 3.25-2.95 (m, 13H), 2.68-2.62 (m, 1H),2.25-2.11 (m, 1H), 1.78-1.54 (m, 3H), 1.20-1.10 (m, 1H), 1.00, 0.97,0.94 (s, 9H total), 0.86-0.75 (m, 2H), 0.51-0.41 (m, 2H); MS (ESI) m/z650.1 (M+H).

S25-11-137:

¹H NMR (400 MHz, CD₃OD) δ 7.52-7.19 (m, 6H), 4.76-4.57 (m, 2H), 4.14 (s,1H), 3.52-3.36 (m, 4H), 3.22-2.90 (m, 11H), 2.67-2.60 (m, 1H), 2.27-2.23(m, 1H), 1.71-1.61 (m, 1H), 1.47 (t, J=14.0 Hz, 3H); MS (ESI) m/z 644.5(M+H).

S25-11-138:

¹H NMR (400 MHz, CD₃OD) δ 7.53-7.28 (m, 6H), 4.76-4.57 (m, 2H), 4.16 (s,1H), 3.68-3.40 (m, 3H), 3.23-2.91 (m, 12H), 2.71-2.61 (m, 1H), 2.28-2.25(m, 1H), 1.71-1.65 (m, 1H), 1.32-1.18 (m, 1H), 0.89-0.78 (m, 2H),0.55-0.45 (m, 2H); MS (ESI) m/z 670.1 (M+H).

S25-11-139:

¹H NMR (400 MHz, CD₃OD) δ 7.29, 7.28 (s, 1H total), 4.83-4.75 (m, 1H),4.71-4.65 (m, 1H), 4.15 (s, 1H), 3.54-3.36 (m, 1H), 3.23-2.98 (m, 12H),2.69-2.61 (m, 1H), 2.42-2.25 (m, 2H), 2.02-1.97 (m, 2H), 1.74-1.62 (m,5H), 1.35-1.16 (m, 3H), 0.87-0.78 (m, 2H), 0.54-0.44 (m, 2H); MS (ESI)m/z 648.1 (M+H).

S25-11-140:

¹H NMR (400 MHz, CD₃OD) δ 7.34 (s, 1H), 5.12-5.03 (m, 2H), 4.16 (s, 1H),3.75-3.73 (m, 1H), 3.25-2.96 (m, 10H), 2.69-2.62 (m, 1H), 2.31-2.25 (m,1H), 1.76-1.65 (m, 2H), 1.61-1.41 (m, 1H), 1.28-1.16 (m, 1H), 1.04-0.95(m, 1H), 0.94-0.73 (m, 6H), 0.55-0.30 (m, 4H); MS (ESI) m/z 646.1 (M+H)

S25-11-141:

¹H NMR (400 MHz, CD₃OD) δ 7.33, 7.32, 7.29 (s, 1H total), 4.85-4.61 (m,2H), 4.15 (s, 1H), 3.21-2.90 (m, 13H), 2.70-2.60 (m, 1H), 2.29-2.25 (m,1H), 1.91-1.60 (m, 7H), 1.41-1.15 (m, 4H), 1.12-0.75 (m, 4H), 0.54-0.40(m, 2H); MS (ESI) m/z 662.1 (M+H)

S25-11-142:

¹H NMR (400 MHz, CD₃OD) δ 7.35, 7.30 (s, 1H total), 4.83-4.59 (m, 2H),4.15 (s, 1H), 3.40-3.35 (m, 1H), 3.24-2.93 (m, 12H), 2.68-2.61 (m, 1H),2.29-2.25 (m, 1H), 2.08-1.92 (m, 1H), 1.85-1.42 (m, 11H), 1.35-1.16 (m,3H), 0.86-0.78 (m, 2H), 0.54-0.41 (m, 2H); MS (ESI) m/z 676.1 (M+H)

S25-11-143:

¹H NMR (400 MHz, CD₃OD) δ 7.31 (s, 1H), 4.82-4.71 (m, 1H), 4.58-4.42 (m,1H), 4.14 (s, 1H), 4.11-4.01 (m, 1H), 3.21-2.97 (m, 11H), 2.68-2.59 (m,1H), 2.48-2.33 (m, 2H), 2.28-2.20 (m, 1H), 2.18-1.60 (m, 5H), 1.21-1.10(m, 1H), 0.85-0.74 (m, 2H), 0.48-0.35 (m, 2H); MS (ESI) m/z 620.1 (M+H).

S25-11-144:

¹H NMR (400 MHz, CD₃OD) δ 7.29, 7.25 (s, 1H total), 4.68-4.62 (m, 1H),4.36-4.30 (m, 1H), 4.12 (s, 1H), 3.15-2.93 (m, 12H), 2.70-2.60 (m, 1H),2.28-2.22 (m, 1H), 1.70-1.60 (m, 1H), 1.51 (d, J=6.4 Hz, 3H), 0.97-0.73(m, 6H), 0.67-0.38 (m, 6H); MS (ESI) m/z 634.1 (M+H)

S25-11-145:

¹H NMR (400 MHz, CD₃OD) δ 7.86-7.72 (m, 2H), 7.57-7.43 (m, 3H), 7.22,7.08 (s, 1H total), 4.64-4.36 (m, 2H), 4.12 (s, 1H), 3.73-3.61 (m, 1H),3.23-2.89 (m, 10H), 2.66-2.48 (m, 1H), 2.30-2.20 (m, 1H), 2.04-1.99 (m,6H), 1.65-1.56 (m, 1H), 1.19, 0.98 (t, J=7.2 Hz, 3H total); MS (ESI) m/z658.1 (M+H).

S25-11-146:

¹H NMR (400 MHz, CD₃OD) δ 7.37 (s, 1H), 5.10 (d, J=14.0 Hz, 1H), 4.75(d, J=14.0 Hz, 1H), 4.15 (s, 1H), 4.10-4.08 (m, 2H), 3.30-2.96 (m, 13H),2.69-2.58 (m, 1H), 2.27-2.23 (m, 1H), 1.69-1.60 (m, 1H), 1.02 (s, 9H);MS (ESI) m/z 626.1 (M+H).

S25-11-147:

¹H NMR (400 MHz, CD₃OD) δ 7.27 (s, 1H), 4.60-4.42 (m, 2H), 4.14 (s, 1H),3.22-2.90 (m, 12H), 2.70-2.62 (m, 1H), 2.27-2.23 (m, 1H), 1.70-1.60 (m,1H), 1.59 (s, 3H), 1.31-1.22 (m, 2H), 1.08-0.87 (m, 2H); MS (ESI) m/z580.1 (M+H).

S25-11-148:

¹H NMR (400 MHz, CD₃OD) δ 7.26 (s, 1H), 4.83-4.66 (m, 2H), 4.13 (s, 1H),3.51-3.40 (m, 2H), 3.21-2.96 (m, 9H), 2.69-2.58 (m, 1H), 2.26-2.22 (m,1H), 1.69-1.60 (m, 1H), 1.59 (s, 3H), 1.48-1.35 (m, 4H), 1.05-0.76 (m,3H); MS (ESI) m/z 594.1 (M+H).

S25-11-149:

¹H NMR (400 MHz, CD₃OD) δ 7.26 (s, 1H), 4.56-4.52 (m, 1H), 4.18-4.13 (m,2H), 3.21-2.97 (m, 9H), 2.66 (s, 3H), 2.65-2.45 (m, 3H), 2.29-2.17 (m,2H), 2.11-2.02 (m, 1H), 1.96-1.90 (m, 2H), 1.69-1.60 (m, 4H); MS (ESI)m/z 594.1 (M+H).

S-25-11-149:

¹H NMR (400 MHz, CD₃OD) δ 7.36, 7.35 (s, 1H total), 4.53-4.36 (m, 2H),4.14 (s, 1H), 3.21-2.96 (m, 11H), 2.76-2.47 (m, 3H), 2.36-2.22 (m, 1H),2.13-2.02 (m, 2H), 2.01-1.88 (m, 2H), 1.68-1.63 (m, 4H), 1.23, 1.12 (t,J=7.2 Hz, 3H total); MS (ESI) m/z 608.1 (M+H).

S25-11-151:

¹H NMR (400 MHz, CD₃OD) δ 7.67-7.27 (m, 5H), 6.88 (s, 1H), 4.11 (s, 1H),4.05 (d, J=13.6 Hz, 1H), 3.96 (d, J=14.0 Hz, 1H), 3.21-2.85 (m, 9H),2.57-2.50 (m, 1H), 2.23-2.13 (m, 1H), 1.90 (m, 6H), 1.64-1.54 (m, 1H);MS (ESI) m/z 630.1 (M+H).

S25-11-152:

¹H NMR (400 MHz, CD₃OD) δ 7.53 (s, 5H), 7.21 (s, 1H), 4.75-4.62 (m, 1H),4.53-4.27 (m, 3H), 4.13 (s, 1H), 3.20-2.85 (m, 9H), 2.79 (s, 3H),2.69-2.57 (m, 1H), 2.25-2.14 (m, 1H), 1.68-1.58 (m, 1H); MS (ESI) m/z616.1 (M+H).

S25-11-153:

¹H NMR (400 MHz, CD₃OD) δ 7.73-7.54 (m, 5H), 7.23, 7.18, 7.13 (s, 1Htotal), 4.87-4.73 (m, 2H), 4.13-4.02 (m, 2H), 3.21-2.88 (m, 9H), 2.79,2.72 (s, 3H total), 2.66-2.52 (m, 1H), 2.30-2.21 (m, 1H), 1.86 (d, J=4.4Hz, 3H), 1.67-1.58 (m, 1H); MS (ESI) m/z 630.0 (M+H).

S25-11-154:

¹H NMR (400 MHz, CD₃OD) δ 7.64-7.50 (m, 5H), 7.16, 7.08 (s, 1H total),5.02-4.98 (m, 1H), 4.68-4.23 (m, 2H), 4.13 (s, 1H), 3.47-3.35 (m, 1H),3.21-2.88 (m, 10H), 2.69-2.54 (m, 1H), 2.26-2.20 (m, 1H), 1.88-1.83 (m,3H), 1.66-1.57 (m, 1H), 1.44-1.33 (m, 3H); MS (ESI) m/z 644.2 (M+H).

S25-11-155:

¹H NMR (400 MHz, CD₃OD) δ 7.17 (s, 1H), 4.21 (d, J=14.4 Hz, 1H), 4.31(d, J=14.0 Hz, 1H), 4.14 (s, 1H), 3.22-2.88 (m, 11H), 2.69-2.57 (m, 1H),2.26-2.23 (m, 1H), 1.68-1.59 (m, 1H), 1.38 (t, J=7.2 Hz, 3H); MS (ESI)m/z 540.1

S25-11-156:

¹H NMR (400 MHz, CD₃OD) δ 7.60-7.45 (m, 5H), 7.21, 7.18 (s, 1H total),5.10-4.93 (m, 1H), 4.72-4.64 (m, 1H), 4.49-4.45 (1H), 4.12 (s, 1H),3.22-2.87 (m, 11H), 2.66-2.55 (m, 1H), 2.26-2.18 (m, 1H), 1.95-1.85 (m,3H), 1.68-1.58 (m, 1H), 1.15-1.08 (m, 1H), 0.90-0.66 (m, 2H), 0.50-0.35(m, 2H); MS (ESI) m/z 670.1 (M+H).

S25-11-157:

¹H NMR (400 MHz, CD₃OD) δ 7.65-7.48 (m, 5H), 7.26, 7.10 (s, 1H total),5.35-5.25 (m, 0.5H), 4.76-4.65 (m, 1.5H), 4.49-4.35 (m, 1H), 4.11 (s,1H), 3.21-2.95 (m, 11H), 2.66-2.54 (m, 1H), 2.26-2.19 (m, 1H), 1.95-1.82(m, 3H), 1.68-1.59 (m, 1H), 1.20-1.01 (m, 1H), 0.91-0.68 (m, 2H),0.48-0.33 (m, 2H); MS (ESI) m/z 670.1 (M+H).

S25-11-158:

¹H NMR (400 MHz, CD₃OD) δ 7.27 (s, 1H), 6.39 (t, J=54.0 Hz, 1H), 4.57(d, J=13.6 Hz, 1H), 4.46 (d, J=13.2 Hz, 1H), 4.14 (s, 1H), 3.67 (t,J=14.4 Hz, 2H), 3.15-2.98 (m, 9H), 2.89 (s, 3H), 2.68-2.60 (m, 1H),2.28-2.23 (m, 1H), 1.69-1.62 (m, 1H); MS (ESI) m/z 590.1 (M+H).

S25-11-159:

¹H NMR (400 MHz, CD₃OD) δ 7.24 (s, 1H), 4.52 (d, J=14.4 Hz, 1H), 4.43(d, J=14.4 Hz, 1H), 4.14 (s, 1H), 4.11-4.04 (m, 2H), 3.15-2.90 (m, 9H),2.68-2.60 (m, 1H), 2.27-2.24 (m, 1H), 1.68-1.62 (m, 1H); MS (ESI) m/z594.1 (M+H).

S25-11-160:

¹H NMR (400 MHz, CD₃OD) δ 7.80-7.78 (m, 2H), 7.64-7.29 (m, 3H), 7.01,6.93 (s, 1H total), 4.52-4.41 (m, 1H), 4.15 (s, 1H), 4.13-4.08 (m, 1H),3.23-2.87 (m, 9H), 2.77 (s, 3H), 2.61-2.48 (m, 1H), 2.25-2.20 (m, 1H),2.05 (m, 6H), 1.66-1.57 (m, 1H); MS (ESI) m/z 644.1 (M+H).

S25-11-161:

¹H NMR (400 MHz, CD₃OD) δ 7.41, 7.38, 7.23 (s, 1H total), 4.76-4.45 (m,2H), 4.16, 4.15 (s, 1H total), 3.62-3.35 (m, 2H), 3.26-2.96 (m, 10H),2.70-2.64 (m, 1H), 2.28-2.24 (m, 1H), 1.67-1.55 (m, 3H), 1.48-1.38 (m,3H), 1.38-1.28 (m, 1H), 1.24 (s, 3H), 0.92 (s, 6H); MS (ESI) m/z 624.1(M+H).

S25-11-162:

¹H NMR (400 MHz, CD₃OD) δ 7.24, 7.23 (s, 1H total), 4.43 (d, J=13.2 Hz,1H), 4.30 (d, J=13.6 Hz, 1H), 4.14 (s, 1H), 3.21-2.88 (m, 9H), 2.69-2.58(m, 1H), 2.27-2.23 (m, 1H), 2.03-1.69 (m, 8H), 1.69-1.61 (m, 1H), 1.49(s, 3H); MS (ESI) m/z 594.1 (M+H).

S25-11-163:

¹H NMR (400 MHz, CD₃OD) δ 7.25 (s, 1H), 4.43 (d, J=13.6 Hz, 1H), 4.28(d, J=12.8 Hz, 1H), 4.14 (s, 1H), 3.11-2.96 (m, 9H), 2.66-2.58 (m, 1H),2.26-2.23 (m, 1H), 2.01-1.94 (m, 2H), 1.78-1.53 (m, 9H), 1.50 (s, 3H);MS (ESI) m/z 608.1 (M+H).

S25-11-164:

¹H NMR (400 MHz, CD₃OD) δ 7.19 (s, 1H), 4.43 (d, J=14.0 Hz, 1H), 4.33(d, J=14.8 Hz, 1H), 4.10 (s, 1H), 3.03-2.95 (m, 11H), 2.69-2.57 (m, 1H),2.26-2.22 (m, 1H), 1.83-1.76 (m, 6H), 1.39-1.25 (m, 4H), 1.11-1.05 (m,2H); MS (ESI) m/z 608.1 (M+H).

S25-11-165:

¹H NMR (400 MHz, CD₃OD) δ 7.19 (s, 1H), 4.45-4.28 (m, 2H), 4.13 (s, 1H),3.21-2.96 (m, 10H), 2.66-2.60 (m, 1H), 2.26-2.15 (m, 2H), 1.95-1.84 (m,3H), 1.78-1.60 (m, 3H), 1.45-1.21 (m, 6H); MS (ESI) m/z 594.1 (M+H).

S25-11-166:

¹H NMR (400 MHz, CD₃OD) δ 7.17 (s, 1H), 4.48 (d, J=14.4 Hz, 1H), 4.30(d, J=14.0 Hz, 1H), 4.04 (s, 1H), 3.48 (t, J=12.4 Hz, 2H), 3.17-2.86 (m,11H), 2.60-2.50 (m, 1H), 2.17-2.13 (m, 1H), 1.92-1.85 (m, 2H), 1.60-1.51(m, 2H), 1.43-1.15 (m, 6H), 0.82 (t, J=7.2 Hz, 3H); MS (ESI) m/z 622.2(M+H).

S25-11-211:

MS (ESI) m/z 650.1 (M+H).

S25-11-168:

¹H NMR (400 MHz, CD₃OD) δ 7.28 (s, 1H), 4.64 (d, J=14.4 Hz, 1H), 4.49(d, J=13.6 Hz, 1H), 4.13 (s, 1H), 4.05-3.75 (m, 4H), 3.51-3.40 (m, 4H),3.15-2.96 (m, 9H), 2.69-2.60 (m, 1H), 2.26-2.22 (m, 1H), 1.68-1.62 (m,1H); MS (ESI) m/z 582.2 (M+H).

S25-11-169:

¹H NMR (400 MHz, CD₃OD) δ 7.26 (s, 1H), 4.57 (d, J=13.6 Hz, 1H), 4.39(d, J=13.6 Hz, 1H), 4.13 (s, 1H), 3.56 (t, J=14.4 Hz, 2H), 3.23-2.95 (m,11H), 2.66-2.59 (m, 1H), 2.26-2.23 (m, 1H), 1.98-1.90 (m, 3H), 1.70-1.60(m, 3H), 1.55-1.45 (m, 2H), 1.01 (d, J=6.4 Hz, 3H); MS (ESI) m/z 594.2(M+H).

S25-11-170:

¹H NMR (400 MHz, CD₃OD) δ 7.23 (s, 1H), 4.44 (q, J=14 Hz, 2H), 4.15 (s,1H), 3.05-2.96 (m, 9H), 2.81-2.79 (m, 1H), 2.64-2.60 (m, 1H), 2.27-2.23(m, 1H), 1.63 (q, J=13.2 Hz, 1H), 1.49 (d, J=6.4 Hz, 3H), 1.11-1.05 (m,1H), 0.83-0.81 (m, 2H), 0.62-0.59 (m, 1H), 0.39-0.35 (m, 1H); MS (ESI)m/z 580.2 (M+H).

S25-11-171:

¹H NMR (400 MHz, CD₃OD) δ 7.24 (s, 1H), 4.46 (d, J=14 Hz, 1H), 4.34 (d,J=13.2 Hz, 1H), 4.15 (s, 1H), 3.36-3.37 (m, 1H), 3.05-2.96 (m, 9H),2.65-2.56 (m, 1H), 2.27-2.21 (m, 2H), 1.68-1.59 (m, 1H), 1.32 (d, J=6.8Hz, 3H), 1.05 (d, J=6.8 Hz, 3H), 1.01 (d, J=6.8 Hz, 3H); MS (ESI) m/z582.3 (M+H).

S25-11-172:

¹H NMR (400 MHz, CD₃OD) δ 7.19 (s, 1H), 4.43 (d, J=14.4 Hz, 1H), 4.33(d, J=14 Hz, 1H), 4.13 (s, 1H), 3.15-2.96 (m, 10H), 2.65-2.61 (m, 2H),2.29-2.23 (m, 2H), 1.96-1.93 (m, 2H), 1.74-1.63 (m, 5H), 1.31-1.29 (m,2H); MS (ESI) m/z 594.5 (M+H).

S25-11-173:

¹H NMR (400 MHz, CD₃OD) δ 7.27 (s, 1H), 5.49 (d, J=52.8 Hz, 1H), 4.55(m, 1H), 4.12 (s, 1H), 3.95-2.43 (m, 4H), 3.04-2.96 (m, 9H), 2.69-2.61(m, 3H), 2.41-2.23 (m, 1H), 2.25-2.22 (m, 1H), 1.69-1.58 (m, 1H); MS(ESI) m/z 584.3 (M+H).

S25-11-174:

¹H NMR (400 MHz, CD₃OD) δ 7.26 (s, 1H), 5.49 (d, J=52.8 Hz, 1H), 4.59(d, J=13.6 Hz, 1H), 4.13 (s, 1H), 3.83-2.79 (m, 4H), 3.04-2.96 (m, 9H),2.65-2.62 (m, 3H), 2.44-2.43 (m, 1H), 2.26-2.22 (m, 1H), 1.69-1.59 (m,1H); MS (ESI) m/z 584.2 (M+H).

S25-11-175:

¹H NMR (400 MHz, CD₃OD) δ 7.25 (s, 1H), 4.54 (d, J=13.2 Hz, 1H), 4.59(d, J=13.2 Hz, 1H), 4.11 (s, 1H), 3.61-3.53 (m, 2H), 3.39-3.34 (m, 6H),3.28-2.81 (m, 9H), 2.67-2.57 (m, 1H), 2.24-1.92 (m, 5H), 1.68-1.58 (m,1H); MS (ESI) m/z 610.0 (M+H).

S25-11-176:

¹H NMR (400 MHz, CD₃OD) δ 7.25 (s, 1H), 4.56 (d, J=14.4 Hz, 1H), 4.42(d, J=14.4 Hz, 1H), 4.12 (s, 1H), 3.89-3.38 (m, 4H), 3.25-2.91 (m, 9H),2.65-2.57 (m, 1H), 2.24-2.21 (m, 1H), 2.12-1.74 (m, 5H), 1.68-1.58 (m,1H); MS (ESI) m/z 596.0 (M+H).

S25-11-177:

¹H NMR (400 MHz, CD₃OD) δ 7.29 (s, 1H), 4.61 (d, J=13.6 Hz, 1H), 4.42(d, J=13.6 Hz, 1H), 4.13 (s, 1H), 3.74-3.61 (m, 2H), 3.29-3.15 (m, 2H),3.04-2.95 (m, 9H), 2.69-2.59 (m, 3H), 2.25-2.15 (m, 4H), 1.69-1.59 (m,1H); MS (ESI) m/z 648.0 (M+H).

S25-11-178:

¹H NMR (400 MHz, CD₃OD) δ 7.25 (s, 1H), 4.41 (d, J=13.6 Hz, 1H), 4.26(d, J=13.6 Hz, 1H), 4.14 (s, 1H), 3.09-2.96 (m, 9H), 2.69-2.58 (m, 1H),2.25-2.22 (m, 1H), 1.81 (s, 2H), 1.68-1.59 (m, 1H), 1.57 (s, 6H), 1.11(s, 9H); MS (ESI) m/z 624.1 (M+H).

S25-11-179:

¹H NMR (400 MHz, CD₃OD) δ 7.14 (s, 1H), 4.60 (d, J=13.6 Hz, 1H), 4.36(d, J=13.2 Hz, 1H), 4.05 (s, 1H), 3.77-3.70 (m, 2H), 3.22-2.79 (m, 13H),2.59-2.49 (m, 1H), 2.17-2.14 (m, 1H), 1.85-1.50 (m, 7H); MS (ESI) m/z606.0 (M+H)

S25-11-180:

¹H NMR (400 MHz, CD₃OD) δ 7.29 (s, 1H), 4.41-4.38 (m, 2H), 4.13 (s, 1H),3.51-3.49 (m, 1H), 3.23-2.91 (m, 9H), 2.69-2.63 (m, 1H), 2.44-2.40 (m,1H), 2.27-2.23 (m, 1H), 1.94-1.82 (m, 2H), 1.69-1.53 (m, 3H), 1.50-1.45(m, 2H), 1.28 (s, 3H), 0.97 (s, 6H); MS (ESI) m/z 648.3 (M+H).

S25-11-181:

¹H NMR (400 MHz, CD₃OD) δ 7.26-7.10 (s, 1H total), 4.46 (d, J=13.2 Hz,1H), 4.33 (d, J=14.0 Hz, 1H), 4.11 (s, 1H), 3.55 (s, 1H), 3.24-2.87 (m,9H), 2.69-2.59 (m, 1H), 2.31-2.21 (m, 3H), 2.02-1.76 (m, 17H), 1.70-1.60(m, 1H); MS (ESI) m/z 646.1.0 (M+H).

S25-11-182:

¹H NMR (400 MHz, CD₃OD) δ 7.11 (s, 1H), 4.34 (d, J=14.8 Hz, 1H), 4.23(d, J=14.8 Hz, 1H), 4.05 (s, 1H), 3.63-3.60 (m, 1H), 3.18-2.88 (s, 9H),2.60-2.50 (m, 1H), 2.17-2.05 (m, 3H), 1.80-1.71 (m, 2H), 1.69-1.61 (m,4H), 1.59-1.52 (m, 1H); MS (ESI) m/z 580.0 (M+H).

S25-11-183:

¹H NMR (400 MHz, CD₃OD) δ 7.12, 7.10 (s, 1H total), 4.33 (d, J=14.0 Hz,1H), 4.22 (d, J=14.4 Hz, 1H), 4.05, 4.04 (s, 1H total), 3.52-3.46 (m,1H), 3.20-2.88 (s, 9H), 2.61-2.52 (m, 1H), 2.27-2.22 (m, 1H), 1.61-1.52(m, 1H), 1.35 (d, J=6.4 Hz, 6H); MS (ESI) m/z 554.0 (M+H).

S25-11-184:

¹H NMR (400 MHz, CD₃OD) δ 7.19 (s, 1H), 4.43-4.39 (m, 1H), 4.33-4.29 (m,1H), 4.12 (s, 1H), 3.23-2.90 (s, 11H), 2.68-2.55 (m, 1H), 2.25-2.22 (m,1H), 2.02-1.91 (m, 1H), 1.87-1.78 (m, 2H), 1.75-1.47 (m, 9H), 1.36-1.28(m, 2H); MS (ESI) m/z 622.0 (M+H).

S25-11-185:

¹H NMR (400 MHz, CD₃OD) δ 7.26 (s, 1H), 4.75-4.65 (m, 1H), 4.58-4.42 (m,1H), 4.12 (s, 1H), 3.72-3.58 (m, 1H), 3.55-3.36 (m, 2H), 3.25-2.95 (s,10H), 2.67-2.55 (m, 1H), 2.26-2.21 (m, 1H), 2.06-1.98 (m, 1H), 1.90-1.82(m, 1H), 1.62-1.51 (m, 5H), 0.93-0.84 (m, 6H); MS (ESI) m/z 622.0 (M+H).

S25-11-186:

¹H NMR (400 MHz, CD₃OD) δ 7.27-7.14 (m, 6H), 4.57 (d, J=14.4 Hz, 1H),4.40 (d, J=14.4 Hz, 1H), 4.07 (s, 1H), 3.66-3.57 (m, 2H), 3.35-3.29 (m,2H), 3.17-2.91 (s, 10H), 2.61-2.51 (m, 1H), 2.20-2.16 (m, 1H), 2.06-1.98(m, 4H), 1.62-1.52 (m, 1H); MS (ESI) m/z 656.3 (M+H).

S25-11-187:

¹H NMR (400 MHz, CD₃OD) δ 7.18 (s, 1H), 4.48 (d, J=14.0 Hz, 1H), 4.30(d, J=14.0 Hz, 1H), 4.05 (s, 1H), 3.56-3.49 (m, 2H), 3.23-2.88 (s, 11H),2.62-2.52 (m, 1H), 2.18-2.14 (m, 1H), 1.92-1.85 (m, 2H), 1.59-1.39 (m,5H), 0.85 (d, J=6.8 Hz, 6H); MS (ESI) m/z 622.1 (M+H).

S25-11-188:

¹H NMR (400 MHz, CD₃OD) δ 7.22 (s, 1H), 4.54 (d, J=13.2 Hz, 1H), 4.38(d, J=14.4 Hz, 1H), 4.07 (s, 1H), 3.47-3.35 (m, 4H), 3.13-2.90 (s, 9H),2.63-2.55 (m, 1H), 2.21-2.15 (m, 1H), 1.88-1.75 (m, 4H), 1.63-1.55 (m,1H), 1.23 (s, 3H); MS (ESI) m/z 610.1 (M+H).

S25-11-189:

¹H NMR (400 MHz, CD₃OD) δ 7.18 (s, 1H), 4.55 (d, J=12.4 Hz, 1H), 4.44(d, J=16.0 Hz, 1H), 4.12 (s, 1H), 3.22-2.80 (m, 13H), 2.67-2.56 (m, 1H),2.25-2.12 (m, 4H), 2.06-1.83 (m, 5H), 1.69-1.59 (m, 1H), 1.40-1.30 (m,3H); MS (ESI) m/z 608.2 (M+H).

S25-11-190:

¹H NMR (400 MHz, CD₃OD) δ 7.24 (s, 1H), 4.80-4.49 (m, 2H), 4.14 (s, 1H),3.25-2.95 (m, 13H), 2.67-2.57 (m, 1H), 2.27-2.22 (m, 1H), 1.88-1.60 (m,3H), 1.25-1.12 (m, 1H), 1.02-0.95 (m, 3H), 0.85-0.75 (m, 2H), 0.48-0.37(m, 2H); MS (ESI) m/z 608.1 (M+H).

S25-11-191:

¹H NMR (400 MHz, CD₃OD) δ 7.25 (s, 1H), 4.81-4.50 (m, 2H), 4.14 (s, 1H),3.41-3.35 (m, 1H), 3.21-2.96 (m, 12H), 2.68-2.58 (m, 1H), 2.27-2.22 (m,1H), 1.83-1.56 (m, 3H), 1.21-1.10 (m, 1H), 1.02-0.93 (m, 7H), 0.85-0.75(m, 2H), 0.52-0.39 (m, 2H); MS (ESI) m/z 636.1 (M+H).

S25-11-192:

¹H NMR (400 MHz, CD₃OD) δ 7.23 (s, 1H), 4.81-4.49 (m, 2H), 4.13 (s, 1H),3.39-3.35 (m, 1H), 3.23-2.98 (m, 12H), 2.69-2.59 (m, 1H), 2.26-2.21 (m,1H), 1.85-1.60 (m, 3H), 1.45-1.35 (m, 2H), 1.23-1.10 (m, 1H), 0.98 (d,J=7.2 Hz, 3H), 0.85-0.75 (m, 2H), 0.49-0.39 (m, 2H); MS (ESI) m/z 622.1(M+H).

S25-11-193:

¹H NMR (400 MHz, CD₃OD) δ 7.24, 7.21 (s, 1H total), 4.60-4.44 (m, 2H),4.13 (s, 1H), 3.22-2.91 (m, 13H), 2.69-2.59 (m, 1H), 2.29-2.09 (m, 2H),1.69-1.60 (m, 1H), 1.45-1.35 (m, 3H), 1.09-0.95 (m, 6H); MS (ESI) m/z596.1 (M+H).

S25-11-194:

¹H NMR (400 MHz, CD₃OD) δ 7.21 (s, 1H), 4.43 (d, J=13.8 Hz, 1H), 4.36(d, J=14.0 Hz, 1H), 4.14 (s, 1H), 3.12-2.88 (m, 11H), 2.69-2.55 (m, 1H),2.28-2.22 (m, 1H), 2.16-2.05 (m, 1H), 1.69-1.58 (m, 1H), 1.09 (d, J=6.8Hz, 6H); MS (ESI) m/z 568.0 (M+H).

S25-11-195:

¹H NMR (400 MHz, CD₃OD) δ 7.25 (s, 1H), 4.47-4.37 (m, 2H), 4.13 (s, 1H),3.28-2.94 (s, 11H), 2.67-2.57 (m, 1H), 2.27-2.22 (m, 1H), 2.00-1.89 (m,6H), 1.67-1.61 (m, 3H), 0.91 (t, J=7.4 Hz, 3H); MS (ESI) m/z 608.0(M+H).

S25-11-196:

¹H NMR (400 MHz, CD₃OD) δ 7.27 (s, 1H), 4.68-4.61 (m, 2H), 4.59-4.51 (m,1H), 4.41-4.39 (m, 1H), 4.15 (s, 1H), 3.99-3.87 (m, 1H), 3.58-3.52 (m,2H), 3.22-2.97 (m, 9H), 2.67-2.60 (m, 2H), 2.27-2.24 (m, 1H), 2.16-2.11(m, 2H), 2.01-1.95 (m, 3H), 1.71-1.61 (m, 1H); MS (ESI) m/z 623.0 (M+H).

S25-11-197:

¹H NMR (400 MHz, CD₃OD) δ 7.26 (s, 1H), 4.56-4.51 (m, 2H), 4.47-4.32 (m,2H), 4.14 (s, 1H), 3.94-3.72 (m, 2H), 3.65-3.52 (m, 2H), 3.22-2.97 (m,9H), 2.67-2.62 (m, 2H), 2.27-2.24 (m, 1H), 2.01-1.98 (m, 4H), 1.71-1.61(m, 1H); MS (ESI) m/z 623.0 (M+H).

S25-11-198:

¹H NMR (400 MHz, CD₃OD) δ 7.30 (s, 1H), 4.67-4.62 (m, 1H), 4.49-4.42 (m,1H), 4.05 (s, 1H), 3.56-3.52 (m, 1H), 3.44-3.31 (m, 1H), 3.05-2.88 (m,9H), 2.58-2.45 (m, 2H), 2.35-2.31 (m, 1H), 2.18-2.15 (m, 1H), 1.69-1.21(m, 11H); MS (ESI) m/z 620.0 (M+H).

S25-11-199:

¹H NMR (400 MHz, CD₃OD) δ 7.19 (s, 1H), 4.67-4.63 (m, 1H), 4.50-4.46 (m,1H), 4.06 (s, 1H), 3.89-3.82 (m, 2H), 3.68-3.62 (m, 2H), 3.16-2.80 (m,9H), 2.69-2.48 (m, 3H), 2.18-2.11 (m, 1H), 1.60-1.50 (m, 1H); MS (ESI)m/z 601.9 (M+H).

S25-11-200:

¹H NMR (400 MHz, CD₃OD) δ 7.28 (s, 1H), 4.61-4.56 (m, 1H), 4.41-4.38 (m,1H), 4.14 (s, 1H), 3.66-3.61 (m, 2H), 3.19-2.99 (m, 11H), 2.67-2.60 (m,1H), 2.28-2.24 (m, 1H), 2.03-1.95 (m, 2H), 1.71-1.61 (m, 3H), 1.48-1.41(m, 1H), 0.93 (s, 9H); MS (ESI) m/z 636.1 (M+H).

S25-11-201:

¹H NMR (400 MHz, CD₃OD) δ 7.47-7.26 (m, 5H), 4.68-4.58 (m, 3H), 4.18 (s,1H), 3.56-3.45 (m, 4H), 3.29-2.99 (m, 11H), 2.69-2.61 (m, 1H), 2.30-2.27(m, 1H), 1.72-1.63 (m, 1H), 1.21-1.11 (m, 1H), 0.82-0.77 (m, 2H),0.43-0.38 (m, 2H); MS (ESI) m/z 682.3 (M+H).

S25-11-202:

¹H NMR (400 MHz, CD₃OD) δ 7.36 (s, 1H), 4.70-4.63 (m, 2H), 4.18 (s, 1H),3.53-3.48 (m, 1H), 3.31-2.94 (m, 12H), 2.69-2.57 (m, 2H), 2.48-2.45 (m,2H), 2.32-2.25 (m, 1H), 2.05-1.98 (m, 6H), 1.70-1.67 (m, 1H), 1.26-1.22(m, 2H), 1.18-1.14 (m, 1H), 1.10-1.04 (m, 2H), 0.88-0.84 (m, 3H),0.72-0.70 (m, 1H), 0.54-0.49 (m, 2H); MS (ESI) m/z 702.3 (M+H).

S25-11-203:

¹H NMR (400 MHz, CD₃OD) δ 7.39, 7.29 (s, 1H total), 4.78-4.65 (m, 1H),4.36-4.34 (m, 1H), 3.91-3.85 (m, 1H), 3.46-3.40 (m, 1H), 4.18 (s, 1H),3.31-2.98 (m, 11H), 2.68-2.63 (m, 1H), 2.32-2.25 (m, 1H), 1.72-1.65 (m,1H), 1.46-1.41 (m, 3H), 1.21-1.15 (m, 3H), 1.08-1.02 (m, 4H), 0.91-0.71(m, 2H), 0.60-0.40 (m, 2H); MS (ESI) m/z 636.0 (M+H).

S25-11-204:

¹H NMR (400 MHz, CD₃OD) δ 7.27 (s, 1H), 4.69-4.50 (m, 2H), 4.41-4.38 (m,1H), 4.24-4.10 (m, 3H), 3.84-3.68 (m, 3H), 3.21-2.96 (m, 10H). 2.66-2.59(m, 1H), 2.42-2.33 (m, 2H), 2.27-2.24 (m, 1H), 1.69-1.63 (m, 1H),1.21-1.08 (m, 1H), 0.87-0.73 (m, 2H), 0.48-0.36 (m, 2H); MS (ESI) m/z636.2 (M+H).

S25-11-205:

¹H NMR (400 MHz, CD₃OD) δ 7.53 (s, 1H), 5.07-5.03 (m, 1H), 4.61-4.58 (m,1H), 4.17 (s, 1H), 4.07-4.03 (m, 1H), 3.21-2.69 (m, 11H), 2.49-2.42 (m,1H), 2.31-2.27 (m, 1H), 2.02-1.62 (m, 8H), 1.33-1.28 (m, 3H), 1.07-0.99(m, 7H), 0.97-0.91 (m, 2H), 0.79-0.68 (m, 2H); MS (ESI) m/z 702.4 (M+H).

S25-11-206:

¹H NMR (400 MHz, CD₃OD) δ 7.22 (s, 1H), 4.46-4.43 (m, 1H), 4.37-4.34 (m,1H), 4.15 (s, 1H), 3.24-2.99 (m, 11H), 2.67-2.46 (m, 3H), 2.28-2.25 (m,1H), 2.18-1.98 (m, 6H), 1.69-1.62 (m, 2H), 1.28 (s, 3H), 1.07 (s, 3H);MS (ESI) m/z 648.3 (M+H).

S25-11-207:

¹H NMR (400 MHz, CD₃OD) δ 7.26 (s, 1H), 4.73-4.69 (m, 1H), 4.58-4.55 (m,1H), 4.16 (s, 1H), 4.01-3.89 (m, 2H), 3.20-2.98 (m, 10H), 2.67-2.57 (m,1H), 2.28-2.25 (m, 1H), 1.69-1.62 (m, 1H), 1.11 (s, 9H); MS (ESI) m/z612.3 (M+H).

S25-11-208:

¹H NMR (400 MHz, CD₃OD) δ 7.18 (s, 1H), 4.48 (d, J=12.0 Hz, 1H), 4.33(d, J=14.0 Hz, 1H), 4.14 (s, 1H), 3.22-2.89 (m, 11H), 2.70-2.59 (m, 1H),2.26-2.20 (m, 1H), 1.85-1.75 (m, 3H), 1.72-1.60 (m, 2H), 1.11 (t, J=7.2Hz, 3H); MS (ESI) m/z 554.1 (M+H).

S25-11-209:

¹H NMR (400 MHz, CD₃OD) δ 7.43, 7.39 (s, 1H total), 4.85-4.80 (m, 0.5H),4.71-4.65 (m, 1.5H), 4.16 (s, 1H), 3.24-2.97 (m, 13H), 2.67-2.61 (m,1H), 2.31-2.25 (m, 1H), 2.15-1.62 (m, 8H), 1.40-1.15 (m, 1H), 0.93-0.75(m, 6H), 0.58-0.45 (m, 2H); MS (ESI) m/z 662.1 (M+H).

S25-11-210:

¹H NMR (400 MHz, CD₃OD) δ 7.24 (s, 1H), 4.76-4.64 (m, 1H), 4.46-4.38 (m,1H), 4.12 (s, 1H), 3.45-3.42 (m, 1H), 3.18-2.94 (m, 11H), 2.65-2.58 (m,1H), 2.33-2.19 (m, 2H), 1.67-1.57 (m, 1H), 1.36-1.22 (m, 6H), 1.10-1.07(m, 6H); MS (ESI) m/z 610.1 (M+H).

Example 26 Synthesis of Compounds Via Scheme 26

The following compounds were prepared according to Scheme 25.

To a solution of compound S25-5 (3.0 g, 7.06 mmol, 1.0 eq.) in MeOH (50mL), was added trimethyl orthoformate (3.74 g, 7.06 mmol, 5.0 eq.) andp-TSA (67 mg, 0.353 mmol, 0.05 eq.). The resulting mixture was refluxedovernight. The solvent was evaporated, the residue was diluted withEtOAc (50 mL), the resulting solution was washed with sat. aq.NaHCO₃/brine (1:1, 50 mL). The organic phase was dried over NaSO₄,filtered and concentrated. The residue was purified with flashchromatography (200-300 mesh, PE/EA=100:1˜50:1) to give the desiredproduct S26-1 (3.3 g, 99%) as a white solid: ¹H NMR (400 MHz, CDCl₃): δ7.43 (d, J=6.8 Hz, 2H), 7.37-7.30 (m, 6H), 7.25-7.19 (m, 1H), 7.07 (d,J=6.8 Hz, 2H), 5.58 (s, 1H), 5.18 (s, 2H), 3.36 (s, 6H), 2.51 (s, 3H).

To a solution of S26-1 (471 mg, 1 mmol, 1.0 eq.) in anhydrous THF (5 mL)was added n-BuLi (2.5 M in hexane, 0.44 mL, 1.1 mmol, 1.1 eq.) slowly at−78° C. After stirred at −78° C. for 30 min, triisopropyl borate (0.46ml, 2.0 mmol, 2.0 eq.) was added. After stirred at −78° C. for 4 h,acetic acid (0.165 mL, 3 mmol, 3.0 eq.) was added. while the resultingmixture was warmed up to 0° C., 30% H₂O₂ (0.27 mL, 2 mmol, 2.0 eq.) wasadded. The resulting mixture was stirred at rt overnight and thenquenched with saturated aqueous NaHSO₃ solution (caution: till thestarch iodide was negative). The resulting solution was extracted withEtOAc (50 mL). The organic phase was washed with saturated aqueousNaHCO₃ (30 mL), H₂O (30 mL), brine (30 mL) and dried over NaSO₄ andfiltered and then concentrated to give the crude product S26-2, whichwas used for next step directly.

To a solution of S26-2 (1.0 mmol, 1.0 eq.) and K₂CO₃ (276 g, 2 mmol, 2.0eq.) in MeCN (10 mL) was added 2-iodopropane (0.615 g, 5 mmol, 5.0 eq.).The resulting mixture was stirred at 80° C. overnight. The reactionmixture was filtered, the filtrate was concentrated. The residue wasdiluted with EtOAc (50 mL) and H₂O (20 mL). The organic phase wasseparated, dried over Na₂ SO₄, filtered and concentrated. The residuewas purified with flash chromatography (200-300 mesh, PE/EA=100:1-50:1)to give the desired product S27-3 (140 mg, 34.6%) as a pale yellowsolid. ¹H NMR (400 MHz, CDCl₃): δ 10.30 (s, 1H), 7.38-7.36 (m, 2H),7.33-7.27 (m, 6H), 7.20-7.17 (m, 1H), 7.02-7.00 (m, 2H), 5.10 (s, 2H),4.12-4.08 (m, 1H), 2.34 (s, 3H), 1.29 (d, J=6.4 Hz, 6H).

To a solution of compound S26-3 (0.25 g, 0.62 mmol, 1.0 eq.) in MeOH (20mL), was added trimethyl orthoformate (0.33 g, 3.11 mmol, 5.0 eq.) andp-TSA (6 mg, 0.031 mmol, 0.05 eq.). The resulting mixture was refluxedovernight. The solvent was evaporated, the residue was diluted withEtOAc (50 mL) and saturated NaHCO₃/brine (1:1, 20 mL). The organic phasewas separated, dried over Na₂SO₄, filtered and concentrated. The residuewas purified by Prep-TLC to give the desired product S26-4 (200 mg, 72%)as a colorless oil: ¹H NMR (400 MHz, CD₃OD): δ 7.45 (d, J=7.2 Hz, 2H),7.37-7.22 (m, 6H), 7.11 (s, 1H), 7.05 (d, J=7.6 Hz, 2H), 5.54 (s, 1H),5.15 (s, 2H), 4.27-4.21 (m, 1H), 3.32 (s, 6H), 2.33 (s, 3H), 1.29 (d,J=6.0 Hz, 6H).

To a solution of diisopropylamine (0.17 mL, 1.2 mmol, 3.0 eq.) and TMEDA(0.3 mL, 2.0 mmol, 5.0 eq.) in THF (3 mL) was added n-BuLi in hexane(2.5 M, 0.48 mL, 1.2 mmol, 3.0 eq.) dropwise at −78° C. After stirred at−78° C. for 30 min, A solution of S26-4 (180 mg, 0.4 mmol, 1.0 eq.) inTHF (2.0 mL) was added. The resulting dark red solution was then stirredat −78° C. for 30 min and then cooled to −100° C., A solution of enone(173 mg, 0.36 mmol, 0.9 eq.) in THF (2.0 mL) was added. The resultingreaction mixture was warmed up to −10° C. naturally over 30 min. Thereaction mixture was quenched with saturated NH₄Cl (50 mL) and thenextracted with EtOAc (50 mL). The organic phase was separated, driedover Na₂SO₄, filtered and concentrated. The residue was purified byPrep-TLC to afford the desired product S26-5 (120 mg, 36%) as a paleyellow solid. ¹H NMR (400 MHz, CDCl₃): δ 7.37-7.33 (m, 4H), 7.26-7.17(m, 5H), 7.13-7.10 (m, 1H), 6.97 (s, 1H), 5.34 (s, 1H), 5.22 (s, 2H),5.07 (dd, J=12.8, 12.4 Hz, 2H), 4.02-3.94 (m, 2H), 3.88 (d, J=10.8 Hz,1H), 3.21 (s, 3H), 3.13 (s, 3H), 0.72-2.70 (m, 1H), 2.41-2.32 (m, 9H),2.00-1.96 (m, 1H), 1.16 (dd, J=6.0, 6.0 Hz, 6H), 0.68 (s, 9H), 0.12 (s,3H), 0.09 (s, 3H).

To a solution of compound S26-5 (120 mg, 0.143 mmol, 1.0 eq.) in THF (2mL) was added 6N HCl (0.17 mL). The resulting reaction solution wasstirred at rt for 1 h. The reaction mixture was diluted with EtOAc (40mL). The resulting mixture was washed with saturated NaHCO₃ (10 mL), andthen brine (10 mL). The organic phase was dried over Na₂ SO₄, filteredand concentrated to give the desired crude product S26-6 as a yellowoil.

To a solution of crude compound S26-6 (0.0715 mmol, 1.0 eq.) in1,2-dichloroethane (5 mL) were added pyrrolidine (25 μL, 0.286 mmol, 4.0eq.) and acetic acid (13 μL, 0.215 mmol, 3.0 eq.). After stirring for 2h at r.t., sodium triacetoxyborohydride (30 mg, 0.0.143 mmol, 2.0 eq.)was added. The resulting reaction mixture was still stirred at r.t. for2 h. The reaction was quenched with saturated aqueous NaHCO₃ and brine(1:1, 20 mL) and then extracted with EtOAc (40 mL). The organic phasewere dried over anhydrous Na₂ SO₄, filtered and concentrated to give thecrude product, which was used for the next step directly.

To the crude product in THF (8 mL) solution was added Aqueous HF (40%, 4mL) in a polypropylene reaction vessel at 23° C. The reaction mixturewas stirred vigorously at 23° C. overnight and poured into saturatedaqueous K₂HPO₄ (150 mL). The reaction mixture was extracted with EtOAc(2×20 mL). The combined organic phases were dried over anhydrous Na₂SO₄,filtered and concentrated. The residue was used in the next stepdirectly without further purification.

To the crude product in HCl/MeOH (4 N, 1 mL) and MeOH (5 mL) was addedPd/C (10 wt %, 50 mg) in one portion at 23° C. The reaction vessel wassealed and purged with H₂ gas (1 atm) for 1 h. The reaction mixture wasthen filtered through a small Celite pad. The filtrate was concentrated.The residue was purified by preparative HPLC to yield compound S26-7-1(13.35 mg, 33.6% for 3 steps) as a yellow solid: ¹H NMR (400 MHz, CD₃OD)δ 7.06 (s, 1H), 4.50 (d, J=12.8 Hz, 1H), 4.33 (d, J=12.8 Hz, 1H),4.16-4.12 (m, 2H), 3.54-3.45 (m, 2H), 3.26-2.98 (m, 11H), 2.36 (dd,J=14.4, 14.0 Hz, 1H), 2.27-2.24 (m, 1H), 2.16-2.10 (m, 2H), 2.09-2.01(m, 2H), 1.65 (ddd, J=13.2, 13.2, 13.2 Hz, 1H), 1.37 (d, J=6.0 Hz, 3H),1.20 (d, J=6.0 Hz, 3H); MS (ESI) m/z 556.1 (M+H).

The following compounds were prepared similarly to S26-7-1.

¹H NMR (400 MHz, CD₃OD) δ 7.01 (s, 1H), 4.35 (d, J=14.0 Hz, 1H),4.18-4.09 (m, 3H), 3.20-2.88 (m, 11H), 2.36 (dd, J=14.4, 14.4 Hz, 1H),2.24 (ddd, J=13.6, 5.2, 2.8 Hz, 1H), 2.09-2.02 (m, 1H), 1.65 (ddd,J=14.0, 14.0, 14.0 Hz, 1H), 1.35 (d, J=6.0 Hz, 3H), 1.20 (d, J=6.0 Hz,3H), 1.03 (d, J=4.4 Hz, 6H); MS (ESI) m/z 558.1 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.04 (s, 1H), 4.53, 4.32 (d, J=13.2 Hz, 1Htotal), 4.46, 4.21 (d, J=13.2 Hz, 1H total), 4.18-4.12 (m, 1H), 4.10 (s,1H), 3.25-2.97 (m, 13H), 2.44-2.35 (m, 1H), 2.26-2.23 (m, 1H), 2.17-2.06(m, 1H), 1.65 (ddd, J=13.2, 13.2, 13.2 Hz, 1H), 1.39-1.35 (m, 6H), 1.20(t, J=7.2 Hz, 3H), 1.03 (d, J=4.4 Hz, 3H), 1.00-0.94 (m, 3H); MS (ESI)m/z 586.1 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.05 (s, 1H), 4.64, 4.08 (d, J=12.8 Hz, 1Htotal), 4.43, 4.35 (d, J=12.8 Hz, 1H total), 4.18-4.13 (m, 2H),3.19-2.99 (m, 11H), 2.80 (s, 3H), 2.39 (dd, J=14.4, 15.2 Hz, 1H),2.29-2.19 (m, 2H), 1.66 (ddd, J=12.4, 12.0, 12.0 Hz, 1H), 1.41-1.36 (m,3H), 1.23-1.17 (m, 3H), 1.10-1.00 (m, 7H); MS (ESI) m/z 572.1 (M+H).

Example 27 Synthesis of Compounds Via Scheme 27

The following compounds were prepared according to Scheme 27.

Sodium borohydride (0.387 g, 10.2 mmol) was added to a suspension ofS1-7 (3.02 g, 6.81 mmol) in MeOH (30 mL). After bubbling ceased andcomplete solution was achieved, the reaction was quenched with NaHCO₃(saturated, aqueous solution) and was extracted with EtOAc (3×). Thecombined EtOAc extracts were dried over sodium sulfate and concentrated.The material was dissolved in CH₂Cl₂ (20 mL) and triphenylphosphine(2.14 g, 8.17 mmol) was added. A solution of carbontetrabromide (2.71 g,8.17 mmol) in CH₂Cl₂ (5 mL) was added dropwise. After stirringovernight, ˜50% conversion was observed. Additional triphenylphosphine(2.14 g, 8.17 mmol) and carbontetrabromide (2.71 g, 8.17 mmol) wereadded. After 1 h, the reaction mixture was concentrated, and the residuewas triturated with toluene (5 times). The combined toluene fractionswere concentrated, and the material was purified by columnchromatography (Biotage 100 g column, 2 to 20% EtOAc in Hexanesgradient). This gave 2.71 g (71%) of the product: R_(f) 0.41 (10%EtOAc/hexanes); ¹H NMR (400 MHz, CDCl₃) δ 7.50-7.46 (m, 2H), 7.40-7.32(m, 5H), 7.29-7.22 (m, 1H), 7.04 (d, J=8.7 Hz, 2H), 5.11 (s, 2H), 4.67(d, J=2.3 Hz, 2H), 2.35 (d, J=2.3 Hz, 3H); MS (ESI) m/z 528.95, 530.95,532.95 (M+Na).

Sodium cyanide (0.104 g, 3.12 mmol) was added to a solution of S27-1-1(1.08 g, 2.12 mmol) in DMF (5 mL) and water (1 mL). The reaction mixturewas heated to 70° C. overnight. Upon cooling to rt, the reaction mixturewas diluted with EtOAc and was washed with NaHCO₃ (saturated, aqueoussolution, 2 times) water (2 times), and brine (1 time). The organicswere dried over sodium sulfate, filtered and concentrated. The materialwas purified by column chromatography (Biotage 50 g column, 5 to 40%EtOAc in Hexanes gradient). This gave 0.82 g (85%) of the product as awhite solid: Rr 0.33 (20% EtOAc/hexanes); MS (ESI) m/z 476.05, 478.04(M+Na).

A solution of S27-2-1 (0.817 g, 1.80 mmol) was added to a suspension ofsodium hydride (60% dispersion in mineral oil, 0.158 g, 3.96 mmol) inDMF (5 mL). After bubbling ceased (˜5 min), iodomethane (0.247 mL, 3.96mmol) was added. After 45 min, the reaction mixture was quenched withNH₄Cl (saturated, aqueous solution) and was diluted with EtOAc. Thelayers were separated, and washed with water (3 times) and brine (1time). The organics were dried over Na₂SO₄, filtered, and concentratedunder reduced pressure. The material was purified by columnchromatography (Biotage 50 g column, 5 to 40% EtOAc in Hexanesgradient). This gave 0.34 g (390/o) of the product: R_(f) 0.53 (20%EtOAc/hexanes); ¹H NMR (400 MHz, CDCl₃) δ 7.50-7.44 (m, 2H), 7.40-7.30(m, 5H), 7.29-7.22 (m, 1H), 7.03 (d, J=8.2 Hz, 2H), 5.10 (s, 2H), 2.33(d, J=2.8 Hz, 3H), 2.02 (d, J=4.1 Hz, 6H); MS (ESI) m/z 504.06, 506.06(M+Na).

Compound S27-3-1 (0.927 g, 1.92 mmol) and mercury (II) acetate (609 mg,1.92 mmol) were heated to 100° C. in acetic acid (25 mL). After heatingovernight, the reaction mixture was heated to 120° C. After 8 h, heatingcontinued overnight at 100° C. Upon cooling to rt, the reaction mixturewas poured into ice water (100 mL). The resulting solid was collected byfiltration and was washed with water (3 times). The solid was dissolvedin CH₂Cl₂ and was dried over Na₂SO₄, filtered, and concentrated underreduced pressure. This gave 930 mg (97%) of the crude product as a whitesolid:

¹H NMR (400 MHz, CDCl₃) δ 7.50-7.42 (m, 2H), 7.40-7.32 (m, 5H),7.28-7.24 (m, 1H), 7.03 (d, J=8.2 Hz, 2H), 5.55-5.35 (br s, 2H), 5.08(s, 2H), 2.33 (d, J=2.7 Hz, 3H), 1.79 (d, J=5.0 Hz, 6H); MS (ESI) m/z522.19, 524.19 (M+Na).

Bis-(trifluoroacetoxy)iodobenzene (178 mg, 0.414 mmol) was added to asolution of S27-4-1 (207 mg, 0.414 mmol) in acetonitrile (0.5 mL) andwater (0.5 mL). After stirring overnight, the reaction mixture wasdiluted with water (5 mL) and was stirred for 30 min. The reactionmixture was diluted with NaHCO₃ (saturated, aqueous solution) and wasextracted with EtOAc (3 times). The combined extracts were dried overNa₂SO₄, filtered, and concentrated under reduced pressure, yieldingS27-5-1 which was used in the next step without purification: ¹H NMR(400 MHz, CDCl₃) δ 7.52-7.48 (m, 2H), 7.40-7.30 (m, 5H), 7.28-7.24 (m,1H), 7.06-7.02 (m, 2H), 5.08 (s, 2H), 2.31 (d, J=3.2 Hz, 3H), 1.74 (d,J=4.6 Hz, 6H); MS (ESI) m/z 472.19, 474.19 (M+H).

Prepared according to the methods of compound S27-5-1, starting fromcompound S15-8: ¹H NMR (400 MHz, CDCl₃) δ 7.46-7.40 (m, 2H), 7.40-7.30(m, 5H), 7.28-7.20 (m, 2H), 7.12-7.08 (m, 2H), 5.16 (s, 2H), 2.48 (s,3H), 2.04 (br s, 2H), 1.61 (s, 6H); MS (ESI) m/z 410.39 (M+H).

Isobutyraldehyde (0.029 mL, 0.32 mmol), acetic acid (0.036 mL, 0.64mmol) and S27-5-1 (100 mg, 0.212 mmol) were stirred in1,2-dichloroethane (2 mL). After 1 h, sodium triacetoxyborohydride (67.4mg, 0.318 mmol) was added. After 1 h, the reaction mixture was dilutedwith NaHCO₃ (saturated, aqueous solution) and was extracted with CH₂Cl₂.The combined extracts were dried over Na₂SO₄, filtered, and concentratedunder reduced pressure. The material was purified by columnchromatography (Biotage 10 g column, 0 to 4% MeOH in CH₂Cl₂ gradient).This gave 77.8 mg (69%) of the product (˜85% pure): R_(f) 0.38 (5%/6MeOH/CH₂C2); ¹H NMR (400 MHz, CDCl₃) δ 7.3-7.7 (m, 2H), 7.40-7.32 (m,5H), 7.26-7.20 (m, 1H), 7.03 (d, J=7.8 Hz, 2H), 5.08 (s, 2H), 2.31 (d,J=3.2 Hz, 3H), 2.00 (d, J=6.9 Hz, 2H), 1.69 (d, J=6.4 Hz, 6H), 1.68-1.58(m, 1H), 0.86 (d, J=6.4 Hz, 6H); MS (ESI) m/z 528.26, 530.26 (M+H).

n-Butyllithium (0.127 mL, 2.2 M/hexanes, 0.279 mmol) was added todiisopropylamine (0.0395 mL, 0.279 mmol) in THF (5 mL) at −40° C. Thereaction mixture was cooled to −78° C., and TMEDA (0.073 mL, 0.48 mmol)was added. A solution of compound S27-6-1 (77 mg, 0.15 mmol) in THF (1mL) was added dropwise. Initially an orange colored solution formed, butthe color faded as the solution was added. Additional lithiumdiisopropylamide (1.8 M solution, 0.155 mL, 0.279 mmol) was added,giving an orange color. The reaction was stirred at −78° C. for 5 min. Asolution of enone S11-9 (58.4 mg, 0.121 mmol) in THF (0.5 mL) was addeddropwise to the reaction mixture. The reaction was stirred from −78° C.to −20° C. for 45 minutes, quenched by saturated aqueous NH₄Cl, andextracted with EtOAc (3 times). The combined EtOAc extracts were dried(sodium sulfate) and concentrated to yield the crude product, which waspurified by preparative reverse phase HPLC on a Waters Autopurificationsystem using a Sunfire Prep C18 OBD column [5 nm, 19×50 mm; flow rate,20 mL/min; Solvent A: H₂O with 0.1% HCO₂H; Solvent B: MeOH with 0.1%HCO₂H; gradient: 80→100% B over 20 min; mass-directed fractioncollection]. Fractions containing the desired product were collected andconcentrated to give 14 mg of compound S27-7-1 (13%): ¹H NMR (400 MHz,CDCl₃) δ 16.0-15.8 (br s, 1H), 7.58-7.45 (m, 4H), 7.40-7.20 (m, 6H),5.36 (s, 2H), 5.00-4.85 (m, 2H), 3.93 (d, J=10.4 Hz, 1H), 3.26-3.18 (m,1H), 3.07-2.96 (m, 1H), 2.60-2.34 (m, 9H), 2.19-2.10 (br m, 1H), 2.01(d, J=4.9 Hz, 2H), 1.76-1.62 (m, 7H), 0.94-0.74 (m, 15H), 0.27 (s, 3H),0.13 (s, 3H); MS (ESI) m/z 916.49, 918.47 (M+H).

A solution of compound S27-7-1 (14.2 mg, 0.0155 mmol) in 1,4-dioxane (1mL) was treated with HF (0.40 mL, 48-50% aqueous solution). Afterstirring overnight, the mixture was poured into a solution of K₂HPO₄(4.8 g) in water (20 mL). This mixture was extracted with EtOAc (3times). The combined extracts were dried over sodium sulfate, filtered,and concentrated under reduced pressure. The material was dissolved inMeOH (1 mL), 1,4-dioxane (1 mL), and 0.5 N HCl/MeOH (0.2 mL). 100% Pd—C(Degussa, 5 mg) was added, and an atmosphere of hydrogen was introduced.After 5 hrs, the reaction mixture was filtered through Celite andconcentrated under reduced pressure. The crude product was purified bypreparative reverse phase HPLC on a Waters Autopurification system usinga Polymerx 10μ RP-γ100 R column [30×21.20 mm, 10 micron, solvent A: 0.05N HCl, solvent B: MeOH, gradient elution with 0→100% B over 20 min;mass-directed fraction collection]. Fractions containing the desiredproduct were concentrated to remove MeOH and were freeze-dried from0.05N HCl in water/CH₃CN to yield 2.4 mg (25%) of compound S27-9-1: ¹HNMR (400 MHz, CD₃OD) δ 6.92 (d, J=6.4 Hz, 1H), 4.15 (s, 1H), 3.26-2.96(m, 9H), 2.68-2.56 (m, 2H), 2.40-2.24 (m, 2H), 2.02-1.94 (m, 1H), 1.83(s, 6H), 1.68-1.58 (m, 1H), 0.99 (dd, J=6.9, 3.7 Hz, 6H); MS (ESI) m/z546.21 (M+H).

The following compounds were prepared according to the methods ofpreparing S27-9-1.

S27-9-2:

¹H NMR (400 MHz, CD₃OD) δ 6.96 (d, J=6.4 Hz, 1H), 4.16 (s, 1H),3.26-2.96 (m, 9H), 2.61 (dd, J=18.4, 5.5 Hz, 2H), 2.40-2.26 (m, 2H),1.87 (s, 6H), 1.70-1.58 (m, 1H), 1.01 (s, 9H); MS (ESI) m/z 560.26(M+H).

Acetaldehyde (0.25 mL, 4.46 mmol) and sodium triacetoxyborohydride (60mg, 0.28 mmol) were added to a solution of S27-9-1 (78.5 mg, 93.7 mmol)in acetic acid (0.5 mL) and CH₂Cl₂ (5 mL). After stirring overnight,additional acetaldehyde (0.25 mL, 4.46 mmol) and sodiumtriacetoxyborohydride (120 mg, 0.56 mmol) were added. After 3 h, thereaction mixture was diluted with pH 7.0 phosphate buffer and wasextracted with CH₂Cl₂ (3 times). The combined extracts were dried oversodium sulfate, filtered, and concentrated under reduced pressure. Thematerial was used directly in the next step: MS (ESI) m/866.78 (M+H).

A solution of compound S27-8-1 (81 mg, 0.094 mmol) in 1,4-dioxane (1 mL)was treated with HF (0.40 mL, 48-50% aqueous solution). After 30 min,the mixture was poured into a solution of K₂HPO₄ (4.8 g) in water (20mL). This mixture was extracted with EtOAc (2 times). The combinedextracts were dried over sodium sulfate, filtered, and concentratedunder reduced pressure. The material was dissolved in MeOH (2 mL),1,4-dioxane (2 mL), and 0.5 N HCl/MeOH (0.2 mL). 10% Pd—C (Degussa, 5mg) was added, and an atmosphere of hydrogen was introduced. After 2hrs, the reaction mixture was filtered through Celite and concentratedunder reduced pressure. The crude product was purified by preparativereverse phase HPLC on a Waters Autopurification system using a Polymerx10μ RP-γ100 R column [30, 21.20 mm, 10 micron, solvent A: 0.05 N HCl,solvent B: MeOH, gradient elution with 20-100% B over 20 min;mass-directed fraction collection]. Fractions containing the desiredproduct were concentrated to remove MeOH and were freeze-dried from0.05N HCl in water/CH₃CN to yield 7.7 mg (13%) of compound S27-9-3: ¹HNMR (400 MHz, CD₃OD) δ 7.13 (d, J=2.8 Hz, 1H), 4.16 (s, 1H), 3.64-3.52(m, 1H), 3.42-3.30 (m, 1H), 3.28-2.94 (m, 11H), 2.42-2.27 (m, 2H),2.04-1.85 (m, 7H), 1.70-1.59 (m, 1H), 1.43 (dd, J=15.1, 7.3 Hz, 3H),0.99 (dd, J=6.4, 5.9 Hz, 3H), 0.86 (dd, J=16.0, 6.0 Hz, 3H); MS (ESI)m/z 574.33 (M+H).

The following compounds were prepared according to the methods ofpreparing S27-9-3.

S27-9-4:

¹H NMR (400 MHz, CD₃OD) δ 7.12 (d, J=4.6 Hz, 1H), 4.16 (s, 1H),3.26-2.88 (m, 16H), 2.42-2.24 (m, 2H), 1.92 (s, 3H), 1.88 (s, 1H),1.70-1.58 (m, 1H), 1.00-0.94 (m, 9H); MS (ESI) m/z 574.32 (M+H).

S27-9-5:

¹H NMR (400 MHz, CD₃OD) δ 7.07 (d, J=4.6 Hz, 1H), 4.17 (s, 1H),3.26-2.95 (m, 12H), 2.84-2.72 (m, 1H), 2.43-2.16 (m, 3H), 1.98-1.80 (m,9H), 1.74-1.44 (m, 5H), 1.20-1.06 (m, 1H), 1.00-0.84 (m, 1H); MS (ESI)m/z 586.33 (M+H).

SX-9-6:

¹H NMR (400 MHz, CD₃OD) δ 7.13 (d, J=6.4 Hz, 1H), 4.17 (s, 1H),3.64-3.52 (m, 1H), 3.45-3.32 (m, 1H), 3.30-2.95 (m, 9H), 2.43-2.26 (m,2H), 2.26-2.10 (m, 1H), 1.98-1.76 (m, 9H), 1.74-1.54 (m, 6H), 1.50-1.40(m, 3H), 1.28-1.16 (m, 1H), 1.00-0.84 (m, 1H); MS (ESI) m/z 600.40(M+H).

S27-9-7:

¹H NMR (400 MHz, CD₃OD) δ 7.23 (s, 1H), 4.20 (s, 1H), 3.50-3.40 (m, 1H),3.26-2.95 (m, 12H), 2.70-2.52 (m, 1H), 2.48-2.30 (m, 2H), 2.22-2.08 (m,1H), 2.06-1.90 (m, 6H), 1.72-1.58 (m, 1H), 1.08-0.99 (m, 6H); MS (ESI)m/z 576.33 (M+H).

Example 28 Synthesis of Compounds Via Scheme 28

The following compounds were prepared according to Scheme 28.

Benzylbromide (0.687 mL, 5.78 mmol, 1.1 equiv) and K₂CO₃ powder (1.09 g,7.88 mmol, 1.5 equiv) were added to a solution of compound S24-2 (1.772g, 5.25 mmol, 1.0 equiv) in acetone (10 mL). The mixture was stirred atrt overnight. The reaction mixture was filter through celite pad toremove most of the solid. Solvents were evaporated and the residue wasdissolved in a mixture of EtOAc (40 mL) and water (1:1). The organiclayer was separated, and the aqueous layer was extracted with EtOAc (10mL×2). The combined organic phase was dried over anhydrous magnesiumsulfate, filtered, and concentrated. The residue was purified by flashcolumn chromatography (5% to 20% EtOAc/hexanes) to afford the desiredproduct S28-1 as white solid (2.213 g, 98%): ¹H NMR (400 MHz, CDCl₃) δ7.49-7.33 (m, 7H), 7.26-7.22 (m, 1H), 7.15-7.04 (m, 3H), 5.10 (s, 2H),3.79 (s, 3H), 2.42 (s, 3H); MS (ESI) m/z 449.13 (M+Na).

A solution of n-BuLi in hexanes (15.64 mL, 2.5 M, 39.1 mmol, 1.1 equiv)was added dropwise to a solution of compound S28-1 (15.18 g, 35.54 mmol,1.0 equiv) in THF (100 mL) at −100° C. under a N₂ atmosphere. Theresulting red solution was stirred at −100° C. for 5 min and then DMF(6.85 mL, 88.9 mmol, 2.5 equiv.) was added dropwise, slowly warmed to 0°C. in 1 hr. Saturated aqueous NH₄Cl was added. The resulting mixture wasextracted three times with EtOAc (50 mL×3). The combined EtOAc extractswere washed with brine, dried (sodium sulfate), and concentrated.Purification of the residue by flash chromatography gave compound S28-2(9.50 g, 71%) as white solid: ¹H NMR (400 MHz, CDCl₃) δ 10.38 (d, J=2.3Hz, 1H), 7.46-7.41 (m, 2H), 7.41-7.31 (m, 5H), 7.29-7.24 (m, 2H),7.11-7.06 (m, 2H), 5.17 (d, J=1.4 Hz, 2H), 3.88 (d, J=2.3 Hz, 3H), 2.42(d, J=1.8 Hz, 3H); MS (ESI) m/z 399.22 (M+Na).

The compound S28-2 (595.6 mg, 1.583 mmol, 1.0 eq.) was dissolved in THF(8 mL), and (S)-(−)-2-methyl-2-propanesulfinamide (217.5 mg, 1.793 mmol,1.1 eq.) was added. Ti(OEt)₄ (0.371 mL, 1.793 mmol, 1.1 eq.) was addedslowly. After stirring overnight, the reaction mixture was poured intobrine (10 mL) with stirring and was then filtered through a Celite pad.The resulting solution was extracted twice with ethyl acetate (10 mL).The combined organic extracts were washed with brine, dried over sodiumsulfate, and concentrated to give the crude intermediate. Purificationof the residue by flash chromatography gave compound S28-3 (647 mg,85.2%) as an orange oil: ¹H NMR (400 MHz, CDCl₃) δ 8.90 (s, 1H),7.47-7.40 (m, 3H), 7.39-7.28 (m, 4H), 7.27-7.21 (m, 1H), 7.18-7.13 (m,1H), 7.12-7.07 (m, 2H), 5.09 (d, J=3.1 Hz, 2H), 3.78 (s, 3H), 2.40 (s,3H), 1.24 (s, 9H); MS (ESI) m/z 480.33 (M+H).

Methylmagnesium bromide (3.0M solution in Et₂O, 0.367 mL, 1.10 mmol) wasadded to a −48° C. solution of S28-3 (264 mg, 0.550 mmol) in CH₂Cl₂ (3.5mL). After 2 h, the solution was allowed to slowly warm to rt and stirovernight. The reaction was quenched with NH₄Cl (saturated, aqueoussolution) and was extracted with EtOAc (1 time). The EtOAc extracts werewashed with brine (1 time), dried over sodium sulfate, filtered andconcentrated. The material was purified by column chromatography(Biotage 10 g column, 50 to 100% EtOAc in Hexanes gradient). This gave179 mg (66%) of product S28-4 as a white solid: R_(f) 0.14 (70%EtOAc/hexanes); ¹H NMR (400 MHz, CDCl₃) δ 7.43-7.28 (m, 7H), 7.26-7.20(m, 1H), 7.10-7.05 (m, 2H), 6.86 (s, 1H), 5.13-4.92 (m, 3H), 3.77 (s,3H), 3.31 (d, J=2.8 Hz, 1H), 2.38 (s, 3H), 1.43 (d, J=6.9 Hz, 3H), 1.18(s, 9H); MS (ESI) m/z 496.34 (M+H).

Compound S28-4 (179 mg, 0.361 mmol) was treated with 0.5M HCl in MeOH (5mL). After 1 h, the reaction mixture was concentrated under reducedpressure. The material was used directly in the next step as thehydrochloride salt: MS (ESI) m/z 392.30 (M+H).

Sodium triacetoxyborohydride (76 mg, 0.36 mmol) was added to a solutionof S28-5 (47 mg, 0.12 mmol) and formaldehyde (37% aqueous solution, 0.5mL) in AcOH (0.5 mL) and CH₂Cl₂ (3 mL). After 30 min, the solution wasdiluted with EtOAc and was washed with NaHCO₃ (saturated, aqueoussolution, 2 times) and brine (1 time). The organics were dried oversodium sulfate, filtered and concentrated. The material was purified bycolumn chromatography (Biotage 10 g column, 0 to 10% MeOH in CH₂Cl₂gradient). This gave 36.8 mg (73%) of product S28-6-1 as a thick oil:R_(f) 0.40 (10% MeOH/CH₂Cl₂); ¹H NMR (400 MHz, CDCl₃) δ 7.47-7.43 (m,2H), 7.39-7.28 (m, 5H), 7.28-7.22 (m, 1H), 7.12-7.06 (m, 2H), 7.06 (s,1H), 5.14 (dd, J=11.4, 2.8 Hz, 2H), 3.71 (s, 3H), 3.64-3.56 (m, 1H),2.39 (s, 3H), 2.24 (s, 6H), 1.32 (d, J=6.4 Hz, 3H); MS (ESI) m/z 420.33(M+H).

1,4-Dibromobutane (0.0285 mL, 0.240 mmol) was added to a solution ofS28-5 (94 mg, 0.24 mmol) and triethylamine (0.134 mL, 0.960 mmol) inCH₃CN (3 mL), and the reaction mixture was heated to 130° C. (sealed).After 30 min, additional 1,4-dibromobutane (0.028 mL, 0.24 mmol) wasadded and heating was continued at 130° C. After 15 min, additional1,4-dibromobutane (0.20 mL, 1.7 mmol) was added and heating wascontinued at 130° C. After 20 min, the reaction mixture was diluted withEtOAc and was washed with NaHCO₃ (saturated, aqueous solution, 2 times)and brine (1 time). The organics were dried over sodium sulfate,filtered and concentrated. The material was purified by columnchromatography (Biotage 10 g column, 0 to 10% MeOH in CH₂Cl₂ gradient).This gave 48.7 mg (46%) of product S28-6-2 as a thick oil: ¹H NMR (400MHz, CDCl₃) δ 7.48-7.39 (m, 2H), 7.37-7.26 (m, 5H), 7.26-7.18 (m, 1H),7.12-7.04 (m, 3H), 5.13 (s, 2H), 3.38 (s, 3H), 3.66-3.56 (m, 1H),2.57-2.47 (m, 2H), 2.44-2.34 (m, 5H), 1.80-1.68 (m, 4H), 1.38-1.30 (m,3H); MS (ESI) m/z 446.73 (M+H).

n-Butyllithium (2.5 M/hexanes, 0.876 mL, 0.219 mmol) was added todiisopropylamine (0.310 mL, 0.219 mmol) in THF (3 mL) at −40° C. Thereaction mixture was cooled to −78° C., and TMEDA (0.048 mL, 0.32 mmol)was added. A solution of compound S28-6-1 (36.8 mg, 0.0877 mmol) in THF(0.5 mL) was added dropwise. The reaction was stirred at −78° C. for 15min. A solution of enone S1-9 (38.5 mg, 0.0800 mmol) in THF (0.5 mL) wasadded dropwise to the reaction mixture. The reaction was stirred from−78° C. to −20° C. for 1 h, quenched by saturated aqueous NH₄Cl, andextracted with EtOAc (1 time). The combined EtOAc extracts were washedwith water (2 times) and brine (1 time), dried (sodium sulfate) andconcentrated. The material was purified by column chromatography(Biotage 10 g column, 0 to 10% MeOH in CH₂Cl₂ gradient). This gave 31.4mg (49%) of product S28-7-1 as a yellow solid: ¹H NMR (400 MHz, CDCl₃) δ16.2 (s, 1H), 7.53-7.45 (m, 4H), 7.40-7.28 (m, 5H), 7.27-7.22 (m, 1H),7.09 (s, 1H), 5.35 (s, 2H), 5.19 (q, J=12.8 Hz, 2H), 4.02 (d, J=10.4 Hz,1H), 3.66 (s, 3H), 3.52-3.46 (m, 1H), 3.26 (dd, J=15.9, 4.9 Hz, 1H),2.99-2.89 (m, 1H), 2.55-2.42 (m, 9H), 2.22-2.10 (m, 7H), 1.34-1.20 (m,3H), 0.83 (s, 9H), 0.27 (s, 3H), 0.13 (s, 3H); MS (ESI) m/z 808.55(M+H).

A solution of compound S28-7-1 (31.4 mg, 0.0389 mmol) in 1,4-dioxane (1mL) was treated with HF (0.40 mL, 48-50% aqueous solution). Afterstirring overnight, the mixture was poured into a solution of K₂HPO₄(4.8 g) in water (20 mL). This mixture was extracted with EtOAc (2times). The combined extracts were dried over sodium sulfate, filtered,and concentrated under reduced pressure. The material was dissolved inMeOH and 0.5 M HCl in MeOH (2 mL) and was concentrated under reducedpressure. The material was dissolved in MeOH (2 mL) and 1,4-dioxane (2mL). 10% Pd—C (Degussa, 5 mg) was added, and an atmosphere of hydrogenwas introduced. After 1 h, the reaction mixture was filtered throughCelite and concentrated under reduced pressure. The crude product waspurified by preparative reverse phase HPLC on a Waters Autopurificationsystem using a Polymerx 10μ RP-γ100 R column [30×21.20 mm, 10 micron,solvent A: 0.05 N HCl, solvent B: CH₃CN, gradient elution with 0→100% Bover 20 min; mass-directed fraction collection]. Fractions containingthe desired product were freeze-dried to yield 18 mg (79%) of compoundSX-6-1: ¹H NMR (400 MHz, CD₃OD) δ 7.01 (s, 1H), 4.67 (q, J=6.9 Hz, 1H),4.13 (s, 1H), 3.80 (s, 3H), 3.24-2.94 (m, 12H), 2.75 (s, 3H), 2.44-2.34(m, 1H), 2.33-2.24 (m, 1H), 1.76-1.59 (m, 4H); MS (ESI) m/z 516.13(M+H).

Prepared from S28-7-2 according to the methods of compound S28-8-1: ¹HNMR (400 MHz, CD₃OD) δ 7.07 (s, 1H), 4.65 (q, J=6.9 Hz, 1H), 4.13 (s,1H), 3.89-3.81 (m, 1H), 3.77 (s, 3H), 3.40-3.31 (m, 1H), 3.29-2.88 (m,12H), 2.44-2.32 (m, 1H), 2.31-2.03 (m, 3H), 2.02-1.92 (m, 1H), 1.76-1.58(m, 4H); MS (ESI) m/z 542.1 (M+H).

Example 29 Synthesis of Compounds Via Scheme 29

The following compounds were prepared according to Scheme 29.

To a solution of S2-4-14 (18 mg, 0.03 mmol) in concentrated H₂SO₄ (1 mL)was added sodium nitrate solution (0.07 mL of 0.5 M concentrated H₂SO₄solution, 0.04 mmol) at 0° C. The mixture was stirred for 20 min andthen transferred dropwise to a stirring diethyl ether solution (100 mL).The yellow precipitation was filtered with celite and washed with ether(30 mL). The precipitation was then flashed with methanol (30 mL) andconcentrated.

To the residue in MeOH/dioxane solution (4:1, 5 mL) was added palladiumon carbon (8 mg, 10 wt %) and HCl in MeOH (0.5 N, 0.1 mL). The reactionwas stirred under H₂ (balloon) at 25° C. for 60 min. The mixture wasfiltered through a small Celite plug and flashed with MeOH. The filtratewas concentrated to yield the crude product. Preparative reverse phaseHPLC purification on a Waters Autopurification system using a PhenomenexPolymerx 10μ RP-1 100A column [10 μm, 150×21.20 mm; flow rate, 20mL/min; Solvent A: 0.05 N HCl/water; Solvent B: MeOH; injection volume:2.9 mL (0.05 N HCl/water); gradient: 0→100% B over 25 min; mass-directedfraction collection]. Fractions with the desired MW, eluting at13.6-15.5 min, were collected and freeze-dried to yield 10.0 mg ofS29-2-1: ¹H NMR (400 MHz, CD₃OD) δ 4.30 (s, 2H), 4.07 (s, 1H), 3.04 (s,3H), 2.97 (s, 3H), 3.15-2.94 (comp, 5H), 2.28-2.03 (comp, 3H), 1.68-1.57(m, 1H), 1.05 (d, J=6.7 Hz, 6H); MS (ESI) m/z 533.29 (M+H).

S29-2-2 was prepared from S2-4-28 according to the procedure forpreparation of S29-2-1: ¹H NMR (400 MHz, CD₃OD) δ 4.68-4.60 (m, 1H),4.20-4.12 (m, 1H), 4.07 (s, 1H), 3.03 (s, 3H), 2.96 (s, 3H), 3.13-2.93(comp, 3H), 2.76 (s, 3H), 2.28-2.16 (m, 2H), 2.00-1.86 (m, 2H),1.68-1.55 (m, 1H), 1.49 (s, 3H), 1.47 (s, 3H), 1.07 (t, J=7.3 Hz, 3H);MS (ESI) m/z 561.36 (M+H).

S29-2-3 was prepared from S2-4-50 according to the procedure forpreparation of S29-2-1: ¹H NMR (400 MHz, CD₃OD) δ 4.40 (s, 2H), 4.08 (s,1H), 3.49-3.20 (m, 4H), 3.04 (s, 3H), 2.96 (s, 3H), 3.14-2.94 (comp,3H), 2.27-2.17 (comp, 2H), 1.78-1.56 (comp, 5H), 1.11 (s, 3H), 1.04 (s,3H); MS (ESI) m/z 573.35 (M+H).

S29-2-4 was prepared from S1-14-61 according to the procedure forpreparation of S29-2-1: ¹H NMR (400 MHz, CD₃OD) δ 4.61 (d, J=14.0 Hz,1H), 4.57 (d, J=14.0 Hz, 1H), 4.09 (s, 1H), 3.55-3.36 (m, 4H), 3.03 (s,3H), 2.95 (s, 3H), 3.13-2.94 (comp, 3H), 2.35-2.26 (m, 1H), 2.26-2.17(m, 1H), 2.08-1.58 (comp, 9H); MS (ESI) m/z 575.30 (M+H).

Example 30 Synthesis of Compounds Via Scheme 30

The following compounds were prepared according to Scheme 30.

To a solution of aldehyde S10-5 (1.0 g, 2.09 mmol) in DMF (10 mL) wasadded NaH (167 mg, 4.18 mmol) and methyl iodide (390 μL, 6.27 mmol). Themixture was stirred at room temperature for 1 h and then quenched withwater (2 mL). The solution was diluted with EtOAc (150 mL), washed withbrine (50 mL×4), dried (Na₂SO₄), and concentrated. The residue waspurified by flash chromatography on silica gel, eluting withhexanes/EtOAc (1:0 to 5:1) to afford imidazole S30-1 (310 mg, 30%yield); ¹H NMR (400 MHz, CDCl₃) δ 10.30 (s, 1H), 7.40-7.24 (comp, 8H),7.04-6.99 (comp, 2H), 5.00-4.80 (m, 2H), 3.19 (s, 1.9H), 3.15 (s, 1.1H),2.40 (d, J=2.4 Hz, 1.9H), 2.38 (d, J=2.4 Hz, 1.1H), 1.50 (s, 3.3H), 1.35(s, 5.7H); MS (ESI) m/z 516.44 (M+Na).

To a solution of aldehyde S30-1 (200 mg, 0.41 mmol) in1,2-dichloroethane (3 mL) was added isobutylamine (119 μL, 1.23 mmol)and acetic acid (92 μL, 1.64 mmol). The mixture was stirred at roomtemperature for 4 h. NaBH(OAc)₃ (254 mg, 1.20 mmol) was added. Thereaction was stirred at room temperature for 15 h. The mixture wasdiluted with EtOAc (20 mL), washed with brine (5 mL×3), dried (Na₂SO₄)and concentrated. The residue was purified by flash chromatography onsilica gel, eluting with hexanes/EtOAc (1:1) to give amine (126 mg, 56%yield); MS (ESI) m/z 551.47 (M+H).

To the amine (126 mg, 0.23 mmol) in DCM (4 mL) was added Boc₂O (150 mg,0.69 mmol) and Et₃N (96 μL, 0.69 mmol). The reaction was stirred at roomtemperature for 4 h and then concentrated. The residue was purified byflash chromatography on silica gel, eluting with hexanes/EtOAc (7:1) toafford 148 mg of S30-2-1; MS (ESI) m/z 673.68 (M+Na).

To a solution of i-Pr₂NH (88 μL, 0.63 mmol) in THF (2 mL) was added asolution of n-BuLi (0.38 mL of a 1.70 M solution in hexanes, 0.63 mmol)dropwise at −78° C. The reaction was allowed to warm to 0° C. by removalof cooling bath, and then cooled to −78° C. TMEDA (93 μL, 0.63 mmol) wasadded, and the mixture was stirred at −78° C. for 5 min. A solution ofamine S30-2-1 (148 mg, 0.23 mmol) in THF (0.5 mL) was added dropwise tothe LDA solution over 5 min. Once addition was complete, the reactionmixture was stirred at −78° C. for 20 min. A solution of enone (100 mg,0.21 mmol) in THF (0.5 mL) was added dropwise over 5 min. The mixturewas slowly warmed to −20° C. over 45 min. The mixture was quenched withsaturated ammonium chloride solution (5 mL), diluted with EtOAc (50 mL),washed with brine (10 mL×3), dried (Na₂SO₄), and concentrated. Theresidue was purified by flash chromatography on silica gel, eluting withhexanes/EtOAc (1:0 to 10:1) to afford 60 mg of compound S30-3-1 (28%0):MS (ESI) m/z 1040.00 (M+H).

To a solution of S30-3-1 (60 mg, 0.06 mmol) in 1,4-dioxane (2 mL) wasadded hydrochloric acid (2 mL of 4 M solution) at room temperature. Themixture was stirred for 8 h. The mixture was diluted with EtOAc (20 mL),washed two times with potassium phosphate dibasic solution (preparedfrom 2 g K₂HPO₄ and 5 mL water), dried (Na₂SO₄) and concentrated to givea crude methyl aniline.

To a solution of methyl aniline in 1,4-dioxane (3 mL) was added HF (0.3mL of 48% solution in water). The mixture was stirred at roomtemperature for 5 h. The mixture was quenched with potassium phosphatedibasic solution (prepared from 2 g K₂HPO₄ and 5 mL water). The aqueouslayer was extracted with EtOAc (10 mL×3). All organic layers werecombined, dried (Na₂SO₄) and concentrated. The residue was dissolved inethyl acetate (5 mL), and hydrochloric acid (1 mL, 0.5 N in methanol)was added. The mixture was concentrated to give the HCl complex.

To the HCl complex in MeOH/dioxane solution (4:1, 5 mL) was addedpalladium on carbon (50 mg, 10 wt %). The reaction was stirred under H₂(balloon) for overnight. The mixture was filtered through a small Celiteplug and flashed with MeOH. The filtrate was concentrated to yield thecrude product. Preparative reverse phase HPLC purification on a WatersAutopurification system using a Phenomenex Polymerx 10μ RP-1 100A column[10 μm, 150×21.20 mm: flow rate, 20 mL/min; Solvent A: 0.05 N HCl/water;Solvent B: MeOH; injection volume: 3.2 mL (0.05 N HCl/water); gradient:0→100% B over 25 min; mass-directed fraction collection]. Fractions withthe desired MW, eluting at 13.3-15.1 min, were collected andfreeze-dried to yield 19.1 mg of S30-4-1: ¹H NMR (400 MHz, CD₃OD) δ 4.52(s, 2H), 4.12 (s, 1H), 3.76-3.56 (m, 1H), 3.05 (s, 3H), 3.04 (s, 3H),2.97 (s, 3H), 3.24-2.94 (comp, 4H), 2.46-2.37 (m, 1H), 2.32-2.24 (m,1H), 2.20-2.09 (m, 1H), 1.73-1.63 (m, 1H), 1.09 (d, J=6.7 Hz, 6H); MS(ESI) m/z 547.34 (M+H).

S30-4-2 was prepared according to the procedure for preparation ofS30-4-1: ¹H NMR (400 MHz, CD₃OD) δ 4.66 (s, 2H), 4.12 (s, 1H), 3.05 (s,3H), 3.01 (s, 3H), 3.01 (s, 3H), 3.00 (s, 3H), 2.97 (s, 3H), 3.22-2.94(comp, 3H), 2.44-2.10 (m, 2H), 1.72-1.60 (m, 1H); MS (ESI) m/z 519.30(M+H).

Example 31 Synthesis of Compounds Via Scheme 31

The following compounds were prepared according to Scheme 31.

To a mixture of S15-5 (3.12 g, 9.71 mmol, 1.0 equiv) and NIS (2.40 g,10.68 mmol, 1.1 equiv) was added MeCN (20 mL) and TFA (224 μL, 2.91mmol, 0.3 equiv). The resulting reaction mixture was stirred at refluxovernight. More NIS (874 mg, 3.88 mmol, 0.4 equiv) and TFA (75 μL, 0.97mmol, 0.1 equiv) were added. The resulting reaction mixture was stirredat reflux overnight, and cooled to rt. The reaction mixture was dilutedwith EtOAc (200 mL), washed with saturated NaHCO₃ solution (70 mL), andsodium thiosulfate solution (2M, 70 mL), and brine (50 mL). Theresulting organic phase was dried over anhydrous sodium sulfate,filtered, and concentrated to afford an orange solid, which wasrecrystallized from EtOAc/MeOH to give the product as a white solid(2.74 g). The mother liquor was concentrated, and the residue waspurified by flash-column chromatography (0-15% ethyl acetate-hexanes) toafford the desired product S31-1 as a white solid (1.03 g, total yield:87%): ¹H NMR (400 MHz, CDCl₃) δ 7.46-7.42 (m, 2H), 7.31-7.26 (m, 1H),7.24-7.22 (m, 2H), 7.18 (s, 1H), 3.89 (s, 3H), 2.64 (s, 3H); MS (ESI)m/z 444.93, 446.95 (M−H).

To compound S31-1 (447 mg, 1.00 mmol, 1.0 equiv), pyrrolidine (0.165 mL,2.00 mmol, 2.0 equiv), cesium carbonate (489 mg, 1.5 mmol, 1.5 equiv),and Xantphos (31.8 mg, 0.055 equiv) in dry dioxane (5 mL) at roomtemperature was added Pd₂(dba)₃ (22.8 mg, 0.05 equiv Pd). The mixturewas purged by bubbling with dry nitrogen gas for 5 min with gentlestirring. The reaction vessel was then heated under nitrogen at 100° C.for 5 hrs with rapid stirring. The resulting mixture was cooled to rt,diluted with water (20 mL), and extracted with EtOAc (10 mL×3). TheEtOAc extracts were dried over sodium sulfate and concentrated underreduced pressure. Flash column chromatography on silica gel with 5%-30%EtOAc/hexanes afforded the desired product S31-2 (156 mg, 40%) as a palecolorless oil; MS (ESI) m/z 390.30 (M+H).

A solution of BBr₃ in dichloromethane (0.6 mL, 1.0 M, 0.6 mmol, 1.5equiv) was added slowly to a solution of the above compound S31-2 indichloromethane (5 mL) at −78° C. The resulting light yellow solutionwas allowed to warm to 0° C. in 30 min and kept at that temperature for10 min (monitored by LC-MS). The reaction mixture was poured intosaturated NaHCO₃ solution (10 mL), stirred at rt for 5 min, andextracted with dichloromethane (10 mL×2). The organic extracts werecombined and dried over anhydrous magnesium sulfate, filtered, andconcentrated to afford the crude phenol, which was used directly in thenext reaction; MS (ESI) m/z 376.27 (M+H).

Benzylbromide (59.3 μL, 0.5 mmol, 1.25 equiv) and K₂CO₃ powder (110 mg,0.8 mmol, 2 equiv) were added to a solution of the above crude phenol(0.4 mmol, 1.0 equiv) in acetonitrile (10 mL). The mixture was stirredat rt overnight. Solvents were evaporated and the residue was dissolvedin a mixture of EtOAc (20 mL) and water (1:1). The organic layer wasseparated, and the aqueous layer was extracted with EtOAc (10 mL×2). Thecombined organic phase was dried over anhydrous magnesium sulfate,filtered, and concentrated. The residue was purified by flash columnchromatography (5% to 25% EtOAc/hexanes) to afford the desired productS31-3 as a colorless oil (151 mg, 81% two steps): ¹H NMR (400 MHz,CDCl₃) δ 7.44-7.35 (m, 7H), 7.26-7.22 (m, 1H), 7.09-7.07 (m, 3H), 5.10(s, 2H), 3.50-3.41 (m, 4H), 2.34 (d, J=2.4 Hz, 3H), 2.00-1.90 (m, 4H);MS (ESI) m/z 466.34 (M+H).

A solution of n-butyllithium in hexanes (0.30 mL, 1.6 M, 0.48 mmol, 1.5equiv) was added to a solution of diisopropylamine (67.3 μL, 0.48 mmol,1.5 equiv) and TMEDA (71.9 μL, 0.48 mmol, 1.5 equiv) in THF (2 mL) at−78° C. The reaction solution was warmed to −20° C. and then re-cooledto −78° C. A solution of compound S31-3 (149 mg, 0.32 mmol, 1.0 equiv)in THF (1.5 mL) was added dropwise via a cannula. The resulting redreaction mixture was then stirred at −78° C. for 10 min, and cooled to−100° C. A solution of enone S11-9 (154 mg, 0.32 mmol, 1.0 equiv) in THF(1 mL) was added to the reaction mixture via a cannula, followed byLHMDS solution (0.4 mL, 1.0 M, 1.2 eq.). The resulting reaction mixturewas allowed to warm to −30° C. over 1.5 hrs, quenched by saturatedaqueous NH₄Cl (10 mL), and extracted with EtOAc (10 mL×3). The organicphase was dried over sodium sulfate, filtered and concentrated. Theresidue was purified by a preparative reverse phase HPLC on a WatersAutopurification system using a Sunfire Prep C18 OBD column [5 μm, 19×50mm; flow rate, 20 mL/min; Solvent A: H₂O with 0.1% HCO₂H; Solvent B:CH₃CN with 0.1% HCO₂H; injection volume: 3.0 mL (CH₃CN); gradient:80→100% B in A over 10 min; mass-directed fraction collection].Fractions containing the desired product were collected and concentratedto yield compound S31-4 (40.1 mg, 14.7%): ¹H NMR (400 MHz, CDCl₃) δ16.00 (br s, 1H), 7.50-7.46 (m, 4H), 7.39-7.27 (m, 6H), 7.10 (s, 1H),5.36 (s, 2H), 5.18, 5.12 (ABq, J=12.8 Hz, 2H), 4.10 (d, J=10.4 Hz, 1H),3.75-3.65 (m, 2H), 3.59-3.50 (m, 2H), 3.37 (dd, J=4.3, 15.9 Hz, 1H),2.88-2.74 (m, 1H), 2.55-2.40 (m, 9H), 2.12 (d, J=14.0 Hz, 1H), 1.99-1.83(m, 4H), 0.84 (s, 9H), 0.28 (s, 3H), 0.14 (s, 3H); MS (ESI) m/z 854.72(M+H).

A solution of phenyllithium in di-n-butyl ether (39 μL, 1.8 M, 0.07mmol, 1.5 equiv) was added dropwise to a solution of compound S31-4 (40mg, 0.047 mmol, 1.0 equiv) in THF (1.5 mL) at −78° C., forming an orangesolution. After 5 min, a solution of n-butyllithium in hexanes (35.3 μL,1.6 M, 0.056 mmol, 1.2 equiv) was added dropwise at −78° C., followed 2min later by the addition of N,N-dimethylformamide (18.1 μL, 5.0 equiv).The resulting dark red reaction mixture was stirred at −78° C. for 1hour. The reaction mixture was allowed to warm to −40° C. LCMS indicateonly about 30% product present in reaction mixture. Saturated aqueousammonium chloride (5 mL) was added dropwise at −40° C. The reactionmixture was allowed to warm to 23° C., diluted with saturated aqueousammonium chloride (˜10 mL), and extracted with EtOAc (2×15 mL). Theorganic extracts were combined, dried over anhydrous sodium sulfate,filtered, and concentrated, affording compound S31-5 as orange oil,which was used directly in the next reactions: MS (ESI) m/z 804.73(M+H).

(R)-2,3,3-trimethyl-butylamine (3.8 μL, 0.03 mmol, 2.0 equiv), aceticacid (4.5 μL, 0.045 mmol, 3.0 equiv) and sodium triacetoxyborohydride(6.4 mg, 0.03 mmol, 2.0 equiv) were added sequentially to a solution ofcompound S31-5 (crude product, 0.014 mmol, 1.0 equiv) in1,2-dichloroethane (2 mL) at 23° C. After stirring for overnight, thereaction mixture was quenched by the addition of saturated aqueoussodium bicarbonate (5 mL) and extracted with dichloromethane (2×10 mL).The combined organic extracts were dried over anhydrous sodium sulfate,filtered, and concentrated. The residue was purified by preparativereverse phase HPLC on a Waters Autopurification system using a SunfirePrep C18 OBD column [5 μm, 19×50 mm; flow rate, 20 mL/min; Solvent A:H₂O with 0.1% HCO₂H; Solvent B: CH₃CN with 0.1% HCO₂H; injection volume:3.0 mL (CH₃CN); gradient: 20→100% B in A over 10 min; mass-directedfraction collection]. Fractions containing the desired product, elutingat 5.6-6.5 min, were collected and freeze-dried to yield compoundS31-6-1 (7.5 mg, 18% for 2 steps): MS (ESI m/z 889.83 (M+H).

Aqueous HF (48-50%, 0.2 mL) was added to a solution of compound S31-6-1(7.5 mg, 0.0084 mmol, 1.0 equiv) in acetonitrile (1.0 mL) in apolypropylene reaction vessel at 23° C. The mixture was stirredvigorously at 23° C. overnight and poured into aqueous K₂HPO₄ (2.0 gdissolved in 10 mL water). The mixture was extracted with EtOAc (3×10mL). The combined organic extracts were dried over anhydrous sodiumsulfate, filtered, and concentrated. The residue was used directly inthe next step without further purification.

Pd—C (10 wt %, 5 mg) was added in one portion into the yellow solutionof the above crude product in a mixture of HCl/MeOH (0.5 N, 0.25 mL) andMeOH (2 mL) at 23° C. The reaction vessel was sealed and purged withhydrogen by briefly evacuating the flask followed by flushing withhydrogen gas (1 atm). The resulting mixture was stirred at 23° C. for 60min. The reaction mixture was then filtered through a small Celite pad.The filtrate was concentrated. The residue was purified by preparativereverse phase HPLC on a Waters Autopurification system using aPhenomenex Polymerx 10μ RP-γ 100A column [10 μm, 150×21.20 mm; flowrate, 20 mL/min; Solvent A: 0.05 N HCl/water; Solvent B: CH₃CN;injection volume: 3.0 mL (0.05 N HCl/water); gradient: 15→60% B over 10min; mass-directed fraction collection]. Fractions containing thedesired product, eluting at 5.8-8.0 min, were collected and freeze-driedto yield compound S31-7-1 (2.77 mg, 54% for 2 steps): ¹H NMR (400 MHz,CD₃OD) δ 7.01 (s, 1H), 4.36 (d, J=12.8 Hz, 1H), 4.14 (d, J=12.8 Hz, 1H),4.12 (s, 1H), 3.56-3.49 (m, 4H), 3.13-2.84 (m, 10H), 2.39-2.12 (m, 2H),2.03-1.91 (m, 4H), 1.70-1.60 (m, 1H), 1.47 (s, 9H), 1.35 (d, J=6.9 Hz,3H), 1.00 (s, 9H); MS (ESI) m/z 597.25 (M+H).

Example 32 Synthesis of Compounds Via Scheme 32

The following compounds were prepared according to Scheme 32.

Compound S16-4a (1.61 g, 3.57 mmol, 1.0 equiv) was dissolved in1,2-dichloroethane (20 mL). Acetaldehyde (1.2 mL, 21.42 mmol, 6.0 equiv)and acetic acid (0.62 mL, 10.71 mmol, 3.0 equiv) were added. Afterstirring at rt for 1 h, sodium triacetoxyborohydride (2.27 g, 10.71mmol, 3.0 equiv) was added. Stirring was continued for 1 hr. Thereaction mixture was poured into saturated aqueous NaHCO₃ and extractedthree times with dichloromethane. The combined organic extracts werewashed with brine, dried over sodium sulfate, and concentrated to givethe crude intermediate. Purification of the residue by flashchromatography gave compound S32-1-1 (1.52 g, 91%) as a white solid: ¹HNMR (400 MHz, CDCl₃) δ 7.45-7.40 (m, 2H), 7.39-7.30 (m, 5H), 7.25-7.20(m, 1H), 7.09 (s, 1H), 7.07-7.03 (m, 2H), 5.08 (s, 2H), 3.23-3.05 (m,4H), 2.42 (s, 3H), 1.00 (t, J=7.1 Hz, 6H); MS (ESI) m/z 468.39 (M+H).

Compound S16-4a (1.61 g, 3.57 mmol, 1.0 equiv) was dissolved in1,2-dichloroethane (20 mL). Acetone (0.786 mL, 10.71 mmol, 3.0 equiv)and acetic acid (0.62 mL, 10.71 mmol, 3.0 equiv) were added. Afterstirring at rt for 1 h, sodium triacetoxyborohydride (1.14 g, 5.35 mmol,1.5 equiv) was added. Stirring was continued for overnight. The reactionmixture was poured into saturated aqueous NaHCO₃ and extracted threetimes with dichloromethane. The combined organic extracts were washedwith brine, dried over sodium sulfate, and concentrated to give thecrude intermediate. Purification of the residue by flash chromatographygave compound (970 mg, 2.14 mmol, 60%) as a white solid: MS (ESI) m/z454.36 (M+H).

The compound was redissolved in 1,2-dichloroethane (20 mL), followed byacetic acid (0.367 mL, 6.41 mmol, 3.0 equiv) and formaldehyde (0.478 mL,37%, 6.41 mmol, 3.0 eq.). After stirring at rt for 1 h, sodiumtriacetoxyborohydride (0.907 mg, 4.28 mmol, 2.0 equiv) was added.Stirring was continued for overnight. The reaction mixture was pouredinto saturated aqueous NaHCO₃ and extracted three times withdichloromethane. The combined organic extracts were washed with brine,dried over sodium sulfate, and concentrated to give the crudeintermediate. Purification of the residue by flash chromatography gavecompound S32-1-2 (1.08 g, 66% for two steps) as a white solid: ¹H NMR(400 MHz, CDCl₃) δ 7.45-7.31 (m, 7H), 7.27-7.22 (m, 1H), 7.09 (s, 1H),7.08-7.04 (m, 2H), 5.09 (s, 2H), 3.60-3.50 (m, 1H), 2.76 (s, 3H), 2.41(s, 3H), 1.15 (d, J=6.4 Hz, 3H), 0.94 (d, J=6.4 Hz, 3H); MS (ESI) m/z468.36 (M+H).

A solution of n-BuLi in hexanes (1.05 mL, 1.6 M, 1.68 mmol, 1.4 equiv)was added dropwise to a solution of i-Pr₂NH (0.235 mL, 1.68 mmol, 1.4equiv) in THF (5 mL) at −78° C. under a N₂ atmosphere. The resultingsolution was stirred at −78° C. for 20 min and −20° C. for 5 min, andthen re-cooled to −78° C. N,N,N′,N′-Tetramethylethylenediamine (TMEDA,0.252 mL, 1.68 mmol, 1.4 equiv) was added, followed by dropwise additionof compound S32-1-1 (620 mg, 1.32 mmol, 1.1 equiv) in THF (3 mL) viasyringe. After complete addition, the resulting dark-red mixture wasstirred for another 15 min at −78° C. A solution of enone S1-9 (580 mg,1.20 mmol, 1.0 equiv) in THF (2 mL) was added dropwise via syringe.LHMDS (1.44 mL, 1.0 M/THF, 1.44 mmol, 1.2 equiv) was then added and thereaction was slowly warmed to −20° C. Saturated aqueous NH₄Cl was added.The resulting mixture was extracted three times with EtOAc. The combinedEtOAc extracts were washed with brine, dried (sodium sulfate), andconcentrated. Purification of the residue by flash chromatography gavecompound S32-2-1 (627 mg, 62%) as light yellow foam: ¹H NMR (400 MHz,CDCl₃) δ 16.0 (s, 1H), 7.52-7.45 (m, 4H), 7.42-7.27 (m, 6H), 7.12 (s,1H), 5.35 (s, 2H), 5.22-5.09 (m, 2H), 4.00 (d, J=9.8 Hz, 1H), 3.62-3.52(m, 1H), 3.30-3.09 (m, 3H), 3.04-2.93 (m, 1H), 2.87-2.75 (m, 1H),2.58-2.30 (m, 9H), 2.10 (d, J=14.0 Hz, 1H), 1.03 (t, J=7.1 Hz, 3H), 0.91(t, J=7.1 Hz, 3H), 0.82 (s, 9H), 0.26 (s, 3H), 0.13 (s, 3H); MS (ESI)m/z 856.50 (M+H).

A solution of phenyllithium in di-n-butyl ether (0.345 mL, 1.8 M, 0.620mmol, 1.5 equiv) was added dropwise to a solution of compound S32-2-1(352 mg, 0.414 mmol, 1.0 equiv) in THF (10 mL) at −78° C., forming anorange solution. After 5 min, a solution of n-butyllithium in hexanes(0.311 mL, 1.6 M, 0.497 mmol, 1.2 equiv) was added dropwise at −78° C.,followed 2 min later by the addition of N,N-dimethylformamide (0.160 mL,2.07 mmol, 5.0 equiv). The resulting dark red reaction mixture wasstirred at −78° C. for 10 min then warm up to −40° C. in 30 min.Saturated aqueous ammonium chloride (10 mL) was added dropwise at −78°C. The reaction mixture was allowed to warm to 23° C., diluted withsaturated aqueous ammonium chloride (˜20 mL), and extracted with EtOAc(2×25 mL). The organic extracts were combined, dried over anhydroussodium sulfate, filtered, and concentrated, affording compound S32-3-1as an orange oil (419 mg, with reduced by-product), which was useddirectly in the next reactions: ¹H NMR (400 MHz, CDCl₃) δ 15.9 (s, 1H),10.31 (s, 1H), 7.50-7.46 (m, 4H), 7.39-7.26 (m, 7H), 5.36 (s, 2H),5.30-5.13 (m, 2H), 4.01 (d, J=11.0 Hz, 1H), 3.62-3.52 (m, 1H), 3.30-3.09(m, 3H), 3.04-2.93 (m, 1H), 2.87-2.75 (m, 1H), 2.58-2.30 (m, 9H), 2.15(d, J=14.0 Hz, 1H), 1.03 (t, J=7.1 Hz, 3H), 0.91 (t, J=7.1 Hz, 3H), 0.82(s, 9H), 0.27 (s, 3H), 0.14 (s, 3H); MS (ESI) m/z 806.76

Compound S32-3-1 (100 mg, 0.05 mmol, 1.0 equiv) was dissolved in1,2-dichloroethane (2.0 mL). Cyclohexylamine (17.2 μL, 0.15 mmol, 3.0equiv) and acetic acid (11.45 μL, 0.20 mmol, 4.0 equiv) were added.After stirring at rt for 1 h, sodium triacetoxyborohydride (31.8 mg,0.15 mmol, 3.0 equiv) was added. Stirring was continued overnight. Thereaction mixture was poured into saturated aqueous NaHCO₃ and extractedthree times with dichloromethane. The combined organic extracts werewashed with brine, dried over sodium sulfate, and concentrated to givethe crude intermediate S32-4-1-1 (27.5 mg), which was used directly inthe next step without further purification: MS (ESI) m/z 889.85 (M+H).

In a plastic vial, the above amine intermediate was dissolved in CH₃CN(1 mL). Aqueous HF (48-50%, 0.25 mL) was added. After stirring at rt for16 hrs, the reaction mixture was poured into aqueous solution (10 mL) ofK₂HPO₄ (2.0 g) and extracted three times with dichloromethane. Thecombined organic phases were washed with brine, dried, and concentratedto yield the crude intermediate: MS (ESI) m/z 775.72 (M+H).

The above crude intermediate was dissolved in MeOH (2 mL) with 0.5 NHCl/MeOH (0.20 mL). Pd—C (10 wt %, 5 mg) was added. The reaction flaskwas briefly evacuated and re-filled with hydrogen. The reaction mixturewas stirred at rt and monitored by LC-MS. After the reaction wascomplete, the mixture was filtered through a small pad of Celite. Thefiltrate was concentrated to give the crude product, which was purifiedby HPLC on a Waters Autopurification system using a Phenomenex Polymerx10μ RP-γ 100 R column [30×21.20 mm, 10 micron; flow rate, 20 mL/min;Solvent A: 0.05 N HCl/water; Solvent B: MeOH; injection volume: 4.0 mL(0.05 N HCl/water); gradient: 20-100% B over 10 min; mass-directedfraction collection]. Fractions containing the desired product werecollected and freeze-dried to give the desired product as a yellow solidS32-6-1-1 (4.35 mg, 7.4% for four steps): ¹H NMR (400 MHz, CD₃OD) δ 7.00(s, 1H), 4.49, 4.32 (ABq, J=14.7 Hz, 2H), 4.08 (s, 1H), 3.22-2.90 (m,13H), 2.39-2.28 (m, 1H), 2.27-2.14 (m, 3H), 1.97-1.86 (m, 2H), 1.79-1.70(m, 1H), 1.69-1.57 (m, 1H), 1.50-1.35 (m, 4H), 1.35-1.19 (m, 2H), 1.08(t, J=6.9 Hz, 3H), 0.99 (t, J=6.9 Hz, 3H); MS (ESI) m/z 597.30 (M+H).

The following compounds were prepared according to the methods forS32-6-1-1, substituting the appropriate amine for cyclohexylamine.

S32-6-1-2:

¹H NMR (400 MHz, CD₃OD) δ 6.98 (s, 1H), 4.48, 4.32 (ABq, J 15.7 Hz, 2H),4.06 (s, 1H), 3.18-2.89 (m, 15H), 2.40-2.28 (m, 1H), 2.24-2.14 (m, 1H),2.15-2.05 (m, 1H), 1.70-1.58 (m, 1H), 1.07 (d, J=6.4 Hz, 6H), 0.99 (t,J=6.9 Hz, 6H); MS (ESI) m/z 571.29 (M+H).

S32-6-1-3:

¹H NMR (400 MHz, CD₃OD) δ 7.05 (s, 1H), 4.49 (s, 2H), 4.09 (s, 1H),3.17-2.93 (m, 14H), 2.40-2.30 (m, 1H), 2.23-2.17 (m, 1H), 1.70-1.57 (m,1H), 1.38 (d, J=6.4 Hz, 3H), 1.13 (t, J=6.9 Hz, 3H), 1.08 (s, 9H), 0.99(t, J=6.9 Hz, 3H); MS (ESI) m/z 599.39 (M+H).

S32-6-1-4:

¹H NMR (400 MHz, CD₃OD) δ 7.05 (s, 1H), 4.50, 4.28 (ABq, J=14.7 Hz, 2H),4.08 (s, 1H), 3.17-2.92 (m, 14H), 2.39-2.30 (m, 1H), 2.24-2.16 (m, 1H),1.70-1.57 (m, 1H), 1.48 (s, 9H), 1.09 (t, J=6.9 Hz, 3H), 1.00 (t, J=6.9Hz, 3H); MS (ESI) m/z 571.29 (M+H).

S32-6-1-5:

¹H NMR (400 MHz, CD₃OD) δ 7.04 (s, 1H), 4.68, 4.52 (ABq, J=14.7 Hz, 2H),4.08 (s, 1H), 3.73-3.59 (m, 2H), 3.17-2.92 (m, 15H), 2.39-2.30 (m, 1H),2.28-2.01 (m, 5H), 1.70-1.57 (m, 1H), 1.08 (t, J=6.9 Hz, 3H), 1.00 (t,J=6.9 Hz, 3H); MS (ESI) m/z 569.29 (M+H).

S32-6-1-6:

¹H NMR (400 MHz, CD₃OD) δ 7.10 (s, 0.5H), 7.07 (s, 0.5H), 4.65 (d,J=12.8 Hz, 0.5H), 4.58 (d, J=12.8 Hz, 0.5H), 4.43 (d, J=12.8 Hz, 0.5H),4.30 (d, J=12.8 Hz, 0.5H), 4.10 (s, 1H), 3.24-2.81 (m, 15H), 2.43-2.33(m, 1H), 2.27-1.99 (m, 5H), 1.71-1.58 (m, 1H), 1.64 (s, 3H), 1.45 (s,3H), 1.12-1.00 (m, 6H); MS (ESI) m/z 597.30 (M+H).

S32-6-1-7:

¹H NMR (400 MHz, CD₃OD) δ 7.09 (s, 1H), 4.68, 4.47 (ABq, J=14.7 Hz, 2H),4.08 (s, 1H), 3.57-3.40 (m, 2H), 3.24-2.90 (m, 15H), 2.41-2.31 (m, 1H),2.23-1.97 (m, 5H), 2.07-1.84 (m, 4H), 1.83-1.70 (m, 4H), 1.69-1.58 (m,1H), 1.08 (t, J=6.9 Hz, 3H), 1.02 (t, J=6.9 Hz, 3H); MS (ESI) m/z 597.37(M+H).

Compound S32-6-2-1 to S32-6-2-3 was prepared similarly from S32-1-2: ¹HNMR (400 MHz, CD₃OD) δ 7.05 (s, 0.4H), 7.04 (s, 0.6H), 4.80-4.64 (m,0.8H), 4.43-4.20 (m, 1.2H), 4.08 (s, 0.4H), 4.07 (s, 0.6H), 3.67-3.53(m, 2H), 3.20-2.78 (m, 15H), 2.52-2.30 (m, 1H), 2.26-2.17 (m, 1H),2.05-1.58 (m, 9H), 1.26 (d, J=6.4 Hz, 1.8H), 1.21 (d, J J=6.4 Hz, 1.2H),0.94 (d, J=6.4 Hz, 1.8H), 0.79 (d, J=6.4 Hz, 1.2H); MS (ESI) m/z 597.35(M+H).

¹H NMR (400 MHz, CD₃OD) δ 7.06 (s, 0.4H), 7.03 (s, 0.6H), 4.70-4.64 (m,0.8H), 4.40-4.20 (m, 1.2H), 4.08 (s, 0.6H), 4.07 (s, 0.4H), 3.18-2.79(m, 14H), 2.49-2.30 (m, 1H), 2.26-2.17 (m, 1H), 1.71-1.58 (m, 1H),1.41-1.20 (m, 6H), 1.08 (s, 4H), 1.05 (s, 5H), 0.98-0.79 (m, 3H); MS(ESI) m/z 599.38 (M+H).

¹H NMR (400 MHz, CD₃OD) δ 6.98 (s, 0.5H), 6.97 (s, 0.5H), 4.58 (d,J=12.8 Hz, 0.5H), 4.45 (d, J=12.8 Hz, 0.5H), 4.31 (d, J=12.8 Hz, 0.5H),4.15 (d, J=12.8 Hz, 0.5H), 4.09 (s, 0.5H), 4.08 (s, 0.5H), 3.17-2.90 (m,11H), 2.86 (s, 1.5H), 2.75 (s, 1.5H), 2.46-2.28 (m, 1H), 2.27-2.13 (m,3H), 1.97-1.85 (m, 2H), 1.70-1.58 (m, 1H), 1.50-1.34 (m, 5H), 1.33-1.16(m, 4H), 0.95 (d, J=6.4 Hz, 1.5H), 0.81 (d, J=6.4 Hz, 1.5H), MS (ESI)m/z 597.37 (M+H).

Example 33 Synthesis of Compounds Via Scheme 33

The following compounds were prepared according to Scheme 33.

Compound S15-8 (2.51 g, 6.59 mmol) was suspended in methanol (25 mL) andsodium borohydride (373 mg, 9.88 mmol) was added in several portions.After gas evolution ceased and complete solution was achieved, thereaction mixture was quenched with NaHCO₃ (saturated, aqueous solution)and was extracted with EtOAc (3×). The organics were dried over Na₂SO₄,filtered, and concentrated under reduced pressure. This gave 2.49 g(99%) of S33-1 as a white solid. ¹H NMR (400 MHz, CDCl₃) δ 7.46-7.32 (m,7H), 7.27-7.21 (m, 1H), 7.13 (s, 1H), 7.07 (d, J=8.7 Hz, 2H), 5.16 (s,2H), 4.77 (d, J=6.4 Hz, 2H), 2.46 (s, 3H), 2.06 (t, J=6.4 Hz, 1H); MS(ESI) m/z 405.15 (M+H).

10% Palladium on carbon (Degussa, 50 mg) was added to a solution ofcompound S33-2 (1.85 g, 4.84 mmol) in EtOAc (10 mL), Methanol (10 mL),and chlorobenzene (1.5 mL) and an atmosphere of hydrogen was introduced.After 5 hours, the reaction mixture was purged with nitrogen and wasfiltered through Celite. The filtrate was concentrated under reducedpressure, yielding the phenol intermediate as a white solid. Theintermediate was dissolved in acetic acid (15 mL) and sodium acetate(0.595 g, 7.26 mmol) was added. Bromine (0.372 mL, 7.26 mmol) was addeddropwise over ˜3 min. After 10 min, the reaction mixture was quenchedwith Na₂S₂O₃ (5% aqueous solution) and was diluted with EtOAc. Thelayers were separated, and the EtOAc layer was washed with water (3×)and brine (1×). The organics were dried over Na₂SO₄, filtered, andconcentrated under reduced pressure. The material was dissolved inacetone (30 mL), and K₂CO₃ (1.34 g, 9.68 mmol) and benzylbromide (0.633mL, 5.32 mmol) were added. The reaction mixture was heated to 50° C.overnight. Upon cooling to rt, the reaction mixture was diluted withEtOAc and was washed with water (3×) and brine (1×). The organics weredried over Na₂SO₄, filtered, and concentrated under reduced pressure.The material was purified by column chromatography (Biotage 50 g column,7 to 60% EtOAc in hexane gradient), yielding 2.03 g (91%) of S33-2. ¹HNMR (400 MHz, CDCl₃) δ 7.51-7.47 (m, 2H), 7.41-7.31 (m, 5H), 7.30-7.23(m, 1H), 7.03 (d, J=8.2 Hz, 2H), 5.12-5.05 (m, 4H), 2.48 (s, 3H), 2.18(t, J=7.1 Hz, 1H); MS (ESI) m/z 482.99, 484.99, 486.99 (M+Na).

Compound S33-2 (195 mg, 0.423 mmol) was dissolved in dichloromethane (4mL) and DMSO (60.1 μL, 0.846 mmol, 2.0 eq.) was added dropwise at −30°C. After stirred for 5 minutes, trifluoroacetic anhydride (TFAA, 0.117mL, 0.846 mmol, 2.0 eq.) was added slowly in 5 min. The reaction mixturewas warmed up to −20° C. and stirred another 15 min. Triethylamine(0.173 mL, 1.27 mmol, 3.0 eq.) was added and reaction mixture was allowto warm up to rt. The reaction mixture was quenched with NH₄Cl(saturated, aqueous solution) and was extracted with EtOAc (3×10 mL).The organics were dried over Na₂SO₄, filtered, and concentrated underreduced pressure. The material was purified by column chromatography(Biotage 10 g column, 5 to 20% EtOAc in hexane gradient), yielding 150mg (76%) of 533-3 and recover 37 mg compound S-33-2. ¹H NMR (400 MHz,CDCl₃) δ 10.34 (s, 1H), 7.51-7.45 (m, 2H), 7.43-7.31 (m, 5H), 7.31-7.23(m, 1H), 7.03 (d, J=8.2 Hz, 2H), 5.13 (s, 2H), 2.49 (s, 3H); MS (ESI)m/z 481.02, 483.02 (M+Na).

To a solution of aldehyde S33-3 (156 mg, 0.34 mmol, 1.0 equiv) in MeOH(4 mL) was added trimethylorthoformate (231 μL, 2.1 mmol, 5.0 equiv) andTsOH (8 mg, 0.1 equiv). The reaction was heated to 65° C. for overnight.The solvent was evaporated. The residue was redissolved in EtOAc (20mL), washed with saturated aqueous NaHCO₃ and brine, dried over sodiumsulfate, and concentrated. Purification of the residue by flashchromatography gave compound S33-4 (163 mg, 94.5%) as a white solid: ¹HNMR (400 MHz, CDCl₃) δ 7.44-7.40 (m, 2H), 7.38-7.30 (m, 5H), 7.25-7.20(m, 1H), 7.09-7.03 (m, 2H), 5.60 (s, 1H), 5.16 (s, 2H), 3.35 (s, 6H),2.46 (s, 3H); MS (ESI) m/z 527.09 (M+Na).

To a solution of compound S33-4 (163 mg, 0.32 mmol, 1.0 equiv) inanhydrous THF (3 mL) was added i-PrMgCl LiCl (0.536 mL, 1.2 M/THF, 0.643mmol, 2.0 equiv) dropwise at −78° C. under a N₂ atmosphere. After 10min, the temperature was raised to 0° C. and the reaction was stirredfor 1 h at 0° C. The reaction mixture was cooled to −60° C. andN-fluorobenzenesulfonimide (304 mg, 0.964 mmol, 3.0 eq.) in 1 mL THFsolution was added slowly. The reaction was warmed to −20° C., stirredfor 30 min at rt, and quenched by saturated aqueous NH₄Cl. The layerswere separated and the aqueous layer was further extracted twice withEtOAc. The combined organic layers were washed with brine, dried oversodium sulfate, filtered, and concentrated. Purification of the residueby flash chromatography gave compound S33-5 (93 mg, 65%) as a whitesolid: ¹H NMR (400 MHz, CDCl₃) δ 7.46-7.42 (m, 2H), 7.40-7.31 (m, 5H),7.26-7.22 (m, 1H), 7.09-7.03 (m, 2H), 5.62 (s, 1H), 5.19 (s, 2H), 3.36(s, 6H), 2.48 (s, 3H); MS (ESI) m/z 467.15 (M+Na).

A solution of n-BuLi in hexanes (196 μL, 1.6 M, 0.313 mmol, 1.5 equiv)was added dropwise to a solution of i-Pr₂NH (43.9 μL, 0.313 mmol, 1.5equiv) in THF (2 mL) at −78° C. under a N₂ atmosphere. The resultingsolution was stirred at −78° C. for 20 min and -20° C. for 5 min, andthen re-cooled to −78° C. N,N,N′,N′-Tetramethylethylenediamine (TMEDA,62.7 μL, 0.418 mmol, 2.0 equiv) was added, followed by dropwise additionof S33-5 (93 mg, 0.209 mmol, 1.0 equiv) in THF (1 mL) via syringe. Aftercomplete addition, the resulting dark-red mixture was stirred foranother hour at −78° C. and then cooled to −100° C. A solution of enoneS1-9 (100.9 mg, 0.209 mmol, 1.0 equiv) in THF (1 mL) was added dropwisevia syringe. The resulting red mixture was slowly warmed to −78° C.LHMDS (0.313 mL, 1.0 M/THF, 0.313 mmol, 1.5 equiv) was then added andthe reaction was slowly warmed to −20° C. Saturated aqueous NH₄Cl wasadded. The resulting mixture was extracted three times with EtOAc. Thecombined EtOAc extracts were washed with brine, dried (sodium sulfate),and concentrated. Purification of the residue by flash chromatographygave the desired product (120 mg, 69%) as light yellow foam: MS (ESI)m/z 833.47 (M+H).

To a solution of the above product (120 mg, 0.144 mmol, 1.0 equiv) inTHF (10 mL) was added 6 N HCl (1.5 mL) at rt. The resulting mixture wasstirred at rt for 2 hrs, diluted with EtOAc, washed with saturatedaqueous NaHCO₃ and brine, dried over sodium sulfate, and concentrated.Purification of the residue by flash chromatography gave crude aldehydeS33-6 as a light yellow foam: MS (ESI) m/z 819.40 [(M+MeOH)+H].

Compound S33-6 (45 mg, 0.057 mmol, 1.0 equiv) was dissolved in1,2-dichloroethane (3.0 mL). Neopentylamine (20 μL, 0.171 mmol, 3.0equiv) and acetic acid (13.6 μL, 0.228 mmol, 4.0 equiv) were added.After stirring at rt for 1 h, sodium triacetoxyborohydride (24.1 mg,0.104 mmol, 2.0 equiv) was added. Stirring was continued overnight. Thereaction mixture was poured into saturated aqueous NaHCO₃ and extractedthree times with dichloromethane. The combined organic extracts werewashed with brine, dried over sodium sulfate, and concentrated to givethe crude intermediate (20 mg), which was used directly in the next stepwithout further purification: MS (ESI) m/z 858.50 (M+H).

In a plastic vial, the above amine intermediate was dissolved in CH₃CN(1 mL). Aqueous HF (48-50%, 0.25 mL) was added. After stirring at rt for16 hrs, the reaction mixture was poured into aqueous solution (10 mL) ofK₂HPO₄ (2.0 g) and extracted three times with dichloromethane. Thecombined organic phases were washed with brine, dried, and concentratedto yield the crude intermediate: MS (ESI) m/z 744.40 (M+H).

The above crude intermediate was dissolved in MeOH (2 mL) with 0.5 NHCl/MeOH (0.4 mL). Pd—C (10 wt %, 20 mg) was added. The reaction flaskwas briefly evacuated and re-filled with hydrogen. The reaction mixturewas stirred at rt and monitored by LC-MS. After the reaction wascomplete, the mixture was filtered through a small pad of Celite. Thefiltrate was concentrated to give the crude product, which was purifiedby HPLC on a Waters Autopurification system using a Phenomenex Polymerx10μ RP-γ 100 R column [30×21.20 mm, 10 micron; flow rate, 20 mL/min;Solvent A: 0.05 N HCl/water; Solvent B: MeOH; injection volume: 4.0 mL(0.05 N HCl/water); gradient: 20-100% B over 10 min; mass-directedfraction collection]. Fractions containing the desired product werecollected and freeze-dried to give the desired product as a yellow solidS33-8-1 (4.5 mg, 14.9% for three steps): ¹H NMR (400 MHz, CD₃OD) δ 6.94(d, J=6.0 Hz, 1H), 4.34 (s, 2H), 4.08 (s, 1H), 3.21-2.92 (m, 3H), 3.03(s, 3H), 2.96 (s, 3H), 2.92 (s, 2H), 2.65-2.52 (m, 1H), 2.25-2.16 (m,1H), 1.68-1.55 (m, 1H), 1.06 (s, 9H); MS (ESI) m/z 532.25 (M+H).

The following compounds were prepared according to the methods forcompound S33-8-1.

S33-8-2:

¹H NMR (400 MHz, CD₃OD) δ 6.97 (d, J=6.0 Hz, 1H), 4.63-4.54 (m, 1H),4.40-4.32 (m, 1H), 4.08 (s, 1H), 3.22-2.86 (m, 13H), 2.64-2.53 (m, 1H),2.24-2.16 (m, 1H), 1.68-1.58 (m, 1H), 1.08 (s, 9H); MS (ESI) m/z 546.28(M+H).

S33-8-3:

¹H NMR (400 MHz, CD₃OD/DCl) δ 6.92 (d, J=5.96 Hz, 1H), 4.30-4.20 (m,2H), 4.08 (s, 1H), 3.18-2.94 (m, 3H), 3.04 (s, 3H), 2.96 (s, 3H), 2.90(dd, J=13.1, 4.6 Hz, 1H), 2.62-2.52 (m, 1H), 2.25-2.14 (m, 1H),1.68-1.56 (m, 1H), 1.47 (s, 9H); MS (ESI) m/z 518.24 (M+H).

The compounds of the invention including those described above are setforth in Figures: FIGS. 2A-2K; FIGS. 3A-3EE; FIGS. 4A-4Z; FIGS. 5A-50;FIGS. 6A-6FF.

Example 34 Antibacterial Activity of Compounds of the Invention

The antibacterial activities for the compounds of the invention werestudied according to the following protocols.

Minimum Inhibitory Concentration Assay Frozen bacterial strains werethawed and subcultured onto Mueller Hinton Broth (MHB) or otherappropriate media (Streplococcus requires blood and Haemophilus requireshemin and NAD). Following incubation overnight, the strains weresubcultured onto Mueller Hinton Agar and again incubated overnight.Colonies were observed for appropriate colony morphology and lack ofcontamination. Isolated colonies were selected to prepare a startinginoculum equivalent to a 0.5 McFarland standard. The starting inoculumwas diluted 1:125 using MHB for further use. Test compounds wereprepared by dilution in sterile water to a final concentration of 5.128mg/mL. Antibiotics (stored frozen, thawed and used within 3 hours ofthawing) and compounds were further diluted to the desired workingconcentrations.

The assays were run as follows. Fifty μL of MHB was added to wells 2-12of a 96-well plate. One hundred μL of appropriately diluted antibioticswas added to well 1. Fifty μL of antibiotics was removed from well 1 andadded to well 2 and the contents of well 2 mixed by pipetting up anddown five times. Fifty L of the mixture in well 2 was removed and addedto well 3 and mixed as above. Serial dilutions were continued in thesame manner through well 12. Fifty μL was removed from well 12 so thatall contained 50 μL. Fifty μL of the working inoculum was then added toall test wells. A growth control well was prepared by adding 50 μL ofworking inoculum and 50 μL of MHB to an empty well. The plates were thenincubated at 37° C. overnight, removed from the incubator and each wellwas read on a plate reading mirror. The lowest concentration (MIC) oftest compound that inhibited the growth of the bacteria was recorded.

Example

1 2 3 4 5 6 7 8 9 10 11 12 [Abt] 32 16 8 4 2 1 0.5 0.25 0.125 0.06 0.030.015 Grow − − − − − + + + + + + + [Abt] = antibiotic concentration inthe well Grow = bacterial growth (cloudiness)

Interpretation: MIC=2 μg/mL

Protocol for Determining Inoculum Concentration (Viable Count)

Ninety μl of sterile 0.9% NaCl was pipetted into wells 2-6 of a 96-wellmicrotiter plate. Fifty 50 μl of the inoculum was pipetted into well 1.Ten μL from was removed from well 1 and added it to well 2 followed bymixing. Ten μL was removed from well two and mixed with the contents ofwell 3 and so on creating serial dilutions through well 6. Ten μL wasremoved from each well and spotted onto an appropriate agar plate. Theplate was placed into a CO₂ incubator overnight. The colonies in spotsthat contain distinct colonies were counted. Viable count was calculatedby multiplying the number of colonies by the dilution factor.

Spot from Well 1 2 3 4 5 6 Dilution 10² 10³ 10⁴ 10⁵ 10⁶ 10⁷ Factor

Bacterial Strains

Fifteen bacterial strains, listed below, were examined in minimuminhibitory concentration (MIC) assays.

Strain Organism Designation Key Properties Staphylococcus aureus SA100ATCC 13709, MSSA, Smith strain Staphylococcus aureus SA101 ATCC 29213,CLSI quality control strain, MSSA Staphylococcus aureus SA191 HA-MRSA,tetracycline-resistant, lung infection model isolate Staphylococcusaureus SA161 HA-MRSA, tetracycline-resistant, tet(M) Staphylococcusaureus SA158 Tetracycline-resistan tet(K) aaaureusaureus StaphylococcusSE164 ATCC 1228, CLSI quality control epidermidis strain,tetracycline-resistant Enterococcus faecalis EF103 ATCC 29212, tet-I/R,control strain Enterococcus faecalis EF159 Tetracycline-resistant,tet(M) Enterococcus faecalis EF327 Wound isolate (US) tet(M)Enterococcus faecium EF404 Blood isolate (US) tet(M) Streptococcus SP106ATCC 49619, CLSI quality control strain pneumoniae Streptococcus SP160Tetracycline-resistant, tet(M) pneumoniae Streptococcus pyogenes SP3122009 clinical isolate, tet(M) Streptococcus pyogenes SP193 S. pyogenesfor efficacy models; tetS; sensitive to sulfonamides Haemophilusinfluenzae HI262 Tetracycline-resistant ampicillin- resistant Moraxellacatarrhalis MC205 ATCC 8176, CLSI quality control strain Escherichiacoli EC107 ATCC 25922, CLSI quality control strain Escherichia coliEC155 Tetracycline-resistant, tet(A) Escherichia coli EC878 MG1655tolC::kan Escherichia coli EC880 lpxA Escherichia coli EC882 impAEscherichia coli EC200 MDR uropathogenic; serotype O17:K52:H18; UMN 026;trimeth/sulfa- R; BAA-1161 Enterobacter cloacae EC108 ATCC 13047, wtEnterobacter cloacae EC603 Urine isolate (Spain) Klebsiella pneumoniaeKP109 ATCC 13883, wt Klebsiella pneumoniae KP153 Tetracycline-resistant,tet(A), MDR, ESBL⁺ Klebsiella pneumoniae KP457 2009 ESBL⁺, CTX-M, OXAProteus mirabilis PM112 ATCC 35659 Proteus mirabilis PM385 Urine ESBL⁺isolate Pseudomonas aeruginosa PA111 ATCC 27853, wt, control strainPseudomonas aeruginosa PA169 Wt, parent of PA170-173 Pseudomonasaeruginosa PA173 PA170 ΔmexX; MexXY-(missing a functional efflux pump)Pseudomonas aeruginosa PA555 ATCC BAA-47, wild type strain PAO1Pseudomonas aeruginosa PA556 ultiple-Mex efflux pump knockout strainPseudomonas aeruginosa PA689 Blood isolate (US) Acinetobacter baumanniiAB110 ATCC 19606, wt Acinetobacter baumannii AB250 Cystic fibrosisisolate, MDR Stenotrophomonas SM256 Cystic fibrosis isolate, MDRmaltophilia Burkholderia cenocepacia BC240 Cystic fibrosis isolate, MDR*MDR, multidrug-resistant; MRSA, methicillin-resistant S. aureus; MSSA,methicillin-sensitive S. aureus; HA-MRSA, hospital-associated MRSA;tet(K), major gram-positive tetracycline efflux mechanism; tet(M), majorgram-positive tetracycline ribosome-protection mechanism; ESBL⁺,extended spectrum β-lactamase

Results

Values of minimum inhibition concentration (MIC) for the compounds ofthe invention are provided in FIGS. 7A-7J; FIGS. 8A-8D; FIGS. 9A-9M;FIGS. 10A-10I; FIGS. 11A-11G.

Biological Testing

Neutropenic Respiratory Infection Models for S. pneumoniae

Compounds were tested in a neutropenic BALB/c murine model of lunginfection challenged with tetracycline-resistant let(M) S. pneumoniaestrain SP160. Mice were made neutropenic by pre-treatment withcyclophosphamide and infected with SP160 via intranasal administration.Mice were dosed orally with 30 mg/kg compound at 2 and 12 hourspost-infection. At 24 hours following initiation of treatment, mice wereeuthanized and bacterial reduction in the lung was quantified by platinglung homogenates. Data was recorded as log₁₀ reduction in lung colonyforming units versus an untreated control group. The results of thetesting are shown in Table A.

TABLE A Bacterial Reduction in the Lung (Log₁₀ change from COMPOUND NO.24 hour control) S2-4-28 −0.06 S15-13-188 −0.22 S15-13-223 −0.12S16-10-79 −4.31 S24-9-21 −0.89

Neutropenic Respiratory Infection Model for MRSA

Compounds were tested in a neutropenic BALB/c murine model of lunginfection challenged with a tetracycline-resistant tet(M) MRSA strainSA191 infected via intranasal administration. At 2 and 12 hours micewere dosed orally with 50 mg/kg compound. At 24 hours followinginitiation of treatment, mice were euthanized and bacterial reduction inthe lung was quantified by plating lung homogenates. Data was recordedas logo reduction in lung colony forming units versus an untreatedcontrol group. The results of the testing are shown in Table B.

TABLE B Bacterial Reduction in the Lung (Log₁₀ change from COMPOUND NO.24 hour control) S29-2-4 −1.29 S16-10-79 −1.27 S24-9-21 −1.98Mouse Systemic Infection Protocol-S. aureus Smith Septicemia

Compounds were screened for antibacterial activity in vivo in a mousesystemic infection (septicemia) model. In the model, CD-1 female mice(18-22 grams) were injected IP with a S. aureus Smith (ATCC 13709)inoculum that results in 0% survival within 24 to 48 hours. Thebacterial dose required to achieve this effect was previouslyestablished through virulence studies. At one hour post infection, micereceived either 3 mg/ml IV or 30 mg/ml PO. Typically, six mice weretreated per dose group. Animal survival was assessed and recorded for 48hours. Percent survival at 48 hours was recorded and PD₅₀ (mg/kg) wasdetermined for each compound tested. The results (% survival or PD50,the dose in mg/kg that prevents 50% of the mice from death) arepresented in Table C.

TABLE C SA Smith SA Smith septicemia survival septicemia IV PO PD50(mg/kg) Compound (3 mg/kg) 30 mg/kg) IV PO S1-14-105 67% 0% S1-14-128100% 100% S1-14-134 50% 17% S1-14-25 33% 17% S1-14-28 33% 17% S1-14-310% 0% S1-14-36 33% 0% S1-14-4 100% 0% S1-14-46 0% 0% S1-14-73 50% 75%S1-14-90 33% 0% S1-14-91 17% 60% S15-13-117 33% 20% S15-13-15 100% 100%3.5 S15-13-16 33% 17% S15-13-17 100% 67% S15-13-182 33% 67% S15-13-18417% 0% S15-13-187 100% 100% S15-13-188 100% 100% 8.3 S15-13-194 100%100% S15-13-203 100% 100% S15-13-215 50% 50% S15-13-221 33% 50%S15-13-222 100% 100% S15-13-223 100% 100% S15-13-225 100% 100%S15-13-226 100% 83% S15-13-227 17% 0% S15-13-23 83% 50% S15-13-4 100%100% 6.2 S15-13-5 50% 17% S15-13-8 67% 50% S16-10-107 100% 100%S16-10-11 100% 100% 10 S16-10-161 100% 100% S16-10-177 100% 100%S16-10-18 17% 0% S16-10-79 100% 100% S19-8-1 100% 100% (1) 0.36 12.2S21-12-1 100% 33 S2-4-11 0% 0% S2-4-12 100% 100% 0.69 2.1 S2-4-14 100%100% 0.84 12.2 S2-4-19 100% 83% 1 14.3 S2-4-21 16% (2) 0% S2-4-25 100%100% 0.35 1.4 (2) S2-4-28 100% 100% 0.62 3 S2-4-29 100% 100% 1 3.5S2-4-30 33% >60 S2-4-33 67% 33% S2-4-41 0% 0% S2-4-50 33% 20% S2-4-50100% 100% 1 10.1 S2-4-57 50% 33% S2-4-60 17% 33% S2-4-62 17% 25% S2-4-65100% 100% 8.4 S2-4-66 100% 100% 8.5 S2-4-7 67% 17% S24-9-10 100% 100%S24-9-17 100% 100% S24-9-19 100% 100% S24-9-21 100% 100% S24-9-23 100%100% S24-9-25 100% 100% S24-9-31 100% 100% S25-11-1 100% 100% S25-11-120% 20% S25-11-171 83% 17% S25-11-48 100% 100% S25-11-56 67% 33%S25-11-68 50% 83% S27-9-5 83% 67% S27-9-7 17% 33% S29-2-4 100% 83%S3-5-5 100% 100% S6-4-1 100% 100%

Kidney Infection Models for Uropathogenic E. Coli EC200 and K.Pneumoniae ESBL Isolate KP453

Compounds were tested in a BALB/c murine kidney infection modelchallenged with tetracycline-resistant E. coli strain uropathogenicED200 via intravenous injection. At 12 and 24 hours post infection micewere treated orally with 2 mg/kg of test compound. For IV administrationtest compound was dosed at 3 mg/kg. Thirty-six hours followinginitiation of treatment, mice were euthanized and bacterial reduction inthe kidney was quantified by plating kidney homogenates. Results arereported in Table D as log₁₀ reduction in colony forming units (CFUs) inthe kidney versus untreated controls (receiving no test compound).

Compounds were also tested in BALB/c murine kidney infection modelchallenged with levofloxacin-resistant, ESBL⁺ strain KP453 viaintravenous injection with 2% carageenen. At 9 and 24 hours postinfection mice were treated orally with 50 mg/kg of test compound. ForIV administration, test compounds were dosed at 20 mg/kg. At 36 hoursfollowing initiation of treatment, mice were euthanized and bacterialreduction in the kidney was quantified by plating homogenates. Resultsare reported in Table D as log₁₀ reduction in colony forming units(CFUs) in the kidney versus untreated controls (receiving no testcompound).

TABLE D KP453 ESBL KP453 EC200 UTI EC200 UTI UTI ESBL UTI Compd. No. IV3 mg/kg PO 2 mg/kg IV 20 mg/kg PO 50 mg/kg S2-4-25 −3.63 @ −1.07, 3 mpk;−2.15^(a) −2.78 A 2 mpk S2-4-19 −1.91 −1.27 S2-4-12 −2.51 −2.15 S2-4-65−4.61 @ −2.28 12 mpk; −3.18 @ 2 mpk S3-5-5 −2.26 −1.01, −1.74^(a)S15-13-15 −2.82 −1.45 S15-13-4 −3.17 −1.69 S15-13-188 −3.48 @ −1.55 3mpk S15-13-187 −3.46 @ −0.98, −1.99^(a) 3 mpk S15-13-194 −3.44 −2.18S15-13-122 −2.64 −1.84 S15-13-223 −2.27 −1.32 S16-10-161 @5 mpk −1.85,−3.09 −1.04, −1.07^(a) −3.99 −2.83 S24-9-17 −2.61 −2.41 S24-9-23 @ 5 mpk−2.99 −2.95 −2.93 −4.34 S24-9-21 @ 5 mpk −2.30 −2.87 −2.16 −4.09S24-9-25 −2.99 −1.71 S25-11-1 −3.97 −1.84 ^(a)Different testing days

Neutropenic Thigh Model

Female CD-1 mice were pre-treated with cyclophosphamide to render themice neutropenic. Mice were infected with S. aureus ATCC 13709 viainjection of 0.1 ml into the right thigh muscle of each mouse. One and ahalf hours post infection mice were treated IV with test compounds indoses ranging from 0.3 to 30 mg/kg or 0.3 to 20 mg/kg. Four mice weretreated with each drug concentration. Twenty-four hours post treatment,mice were euthanized by CO₂ inhalation. The right thighs of the micewere aseptically removed, weighed, homogenized, serially diluted, andplated on TSA medium. The plates were incubated overnight at 37° C. in5% CO₂. Colony forming units per gram of thigh was calculated byenumerating the plated colonies then adjusting for serial dilutions andthe weight of the thigh. Data was recorded as log₁₀ reduction in colonyforming units versus an untreated control group and is presented inTable E.

TABLE E COMPOUND NO. log₁₀ REDUCTION S2-4-14 3.68 S2-4-25 4.1 22-4-294.35

Pharmacokinetic Studies in Rats

Test compounds were evaluated in fasted (no food for 18 hours prior todosing) male Sprague Dawley rats (3 animals per group) by administrationof 1 mg/kg intravenously into the jugular vein and 10 mg/jg by oralgavage. Ten plasma samples were drawn for each dosing route up to 24hours into heparin-coated vacutainer tubes. The plasma concentrations ofthe test compounds were quantified by LC/MS/MS using an internalstandards. WinNONLIN was used to determine PK parameters ±standarddeviation (AUC, Cmax, CL, Vss and % oral bioavailabilty (% F) and areset forth in Table F.

TABLE F Oral Rat PK Cmpd. No. 10 mg/kg IV Rat PK 1 mg/kg S2-4-14 Cmax543; AUC 6160; 13.7% Cmax 667; AUC (% F) 4432; Cl 233; Vss 1.4 S2-4-25Cmax 76.7; AUC 826; 9.1% Cmax 214; AUC (% F) 838; Cl 1164; Vss 6.6 12 hurine 11 ug/mL S2-4-28 Cmax 381; AUC 4381; 44.7% Cmax 170; AUC (% F)970; Cl 1056; Vss 5.7; S2-4-29 Cmax 171; AUC 1597; 25.4% Cmax 112; AUC(% F) 616; Cl 1589; Vss 9.2 S2-4-19 Cmax 572; AUC 4981; 14.9% Cmax 518;AUC (% F) 3321; Cl 300; Vdss 1.6 S2-4-12 Cmax 117; AUC 1163; 14.6% Cmax126; AUC (% F) 754; Cl 1277; Vdss 9.3 S15-13-15 Cmax 162; AUC 2263;21.0% Cmax 154; AUC (% F) 1104; Cl 927; Vdss 6.4 S16-10-161 Cmax 465;AUC 4442; 31.6% Cmax 689; AUC (% F) 1307; Cl 768; Vdss 4.96 S24-9-23Cmax 310; AUC 2226; 12.2% Cmax 795; AUC (% F) 1831; Cl 555.6; Vdss 3.9

SA MIC90

FIGS. 1A-1C provides the results of testing selected compounds againstselected groups isolates as indicated in the figure to determine theminimal inhibitory concentration (MIC) of test compounds for 90%0/of theisolates (MIC₉)). MICs were performed by microtiter broth dilution in a96-well format according to Clinical Laboratory Standards Institute(CLSI) guidelines, as described above.

Viable counts were determined by 10-fold serial dilution. Dilutions wereprepared in sterile 0.9% NaCl. Ten microliters of the inoculum and ofeach of 5 dilutions were plated onto blood or Mueller Hinton agarplates, incubated overnight at 37° C. with 5% CO₂, and counted. Resultsare shown in FIGS. 1A-1C.

Monkey PK

Compounds S24-9-23 and S16-10-161 were evaluated in 3 non-naïvecynomolgus monkeys. Each animal received a single IV dose of 1 mg/kg andafter a 7-day washout, received a single PO dose of 10 mg/kg. Nine toten plasma samples were drawn for each dosing route up to 24 hours intoheparin-coated vacutainer tubes. Dose formulations were verified with a5-point calibration curve. The plasma concentration of the compound wasquantified by LC/MS/MS using an internal standard. WinNonLin was used todetermine individual and mean PK parameters±standard deviation (% F(oral bioavailability), Cmax, Tmax, CL, Vss, AUC. Results were asfollows: For S24-9-23 oral: Cmax=1350 ng/mL; AUC=22767 ng·hr/mL; %F=36.8% and IV: Cmax=1373 ng/mL; AUC=7070 ng·h/mL; Cl=144 mL/hr/kg,Vdss=3.4 L/kg. For S16-10-161 oral: Cmax=982 ng/mL; AUC=26000 ng-hr/mL;% F=42.7% and IV: Cmax=861; AUC=5677 ng·h/mL; Cl=183.6 mL/hr;Vdss=4.047.

While this invention has been particularly shown and described withreferences to example embodiments thereof, it will be understood bythose skilled in the art that various changes in form and details may bemade therein without departing from the scope of the inventionencompassed by the appended claims.

1-25. (canceled)
 26. A compound of Formula (II):

or a pharmaceutically acceptable salt thereof, wherein: X is selectedfrom fluoro or chloro; R^(1a) is hydrogen; and R² and R³ taken togetherwith the nitrogen atom to which they are bound form a (4-7 membered)monocyclic heterocylic ring, or a (6-13 membered) bicyclic heterocylicring, wherein the (4-7 membered) monocyclic heterocylic ring or the(6-13 membered) bicyclic heterocyclic ring is optionally substitutedwith one or more substituents independently selected from C₃-C₁₀carbocyclyl, (4-13 membered) heterocyclyl, fluoro, chloro, —OH, —C₁-C₄fluoroalkyl, —C₁-C₄ alkyl, —O—C₃-C₁₀ carbocyclyl, —O-(4-13 membered)heterocyclyl, —C₀-C₄ alkylene-O—C₁-C₄ alkyl, —C₀-C₄ alkylene-O—C₁-C₄fluoroalkyl, ═O, —C(O)—C₁-C₄ alkyl, —C(O)N(R⁴)(R⁵), —N(R⁴)—C(O)—C₁-C₄alkyl, and —C₀-C₄ alkylene-N(R⁴)(R⁵), and wherein each carbocyclyl orheterocyclyl substituent is optionally substituted with fluoro, chloro,—OH, C₁-C₄ fluoroalkyl, C₁-C₄ alkyl, —O—C₁-C₄ alkyl, —O—C₁-C₄fluoroalkyl, —NH₂, —NH(C₁-C₄ alkyl), or —N(C₁-C₄ alkyl)₂; and each of R⁴and R⁵ is independently selected from hydrogen and C₁-C₄ alkyl; or R⁴and R⁵ taken together with the nitrogen atom to which they are boundform a (4-7 membered) heterocylic ring optionally comprising oneadditional heteroatom selected from N, S and O, wherein the (4-7membered) heterocylic ring is optionally substituted with fluoro,chloro, —OH, fluoro-substituted C₁-C₄ alkyl, —C₁-C₄ alkyl, or —C₁-C₄alkylene-O—C₁-C₄ alkyl, and is optionally fused to phenyl.
 27. Thecompound of claim 26, wherein: R² and R³ taken together with thenitrogen atom to which they are bound form a ring selected frompyrrolidine, piperidine, piperazine or morpholine, wherein the ring isoptionally substituted with one or more substituents independentlyselected from fluoro, —OH, —C₁-C₃ alkyl and —C₁-C₃ alkylene-O—C₁-C₃alkyl, and wherein the ring is optionally fused to phenyl or spirofusedto cyclopropyl.
 28. The compound of claim 27, wherein: R² and R³ takentogether with the nitrogen atom to which they are bound form a ringselected from pyrrolidine and piperidine.
 29. The compound of claim 28,wherein X is chloro.
 30. The compound of claim 29, wherein: R² and R³taken together with the nitrogen atom to which they are bound form aring selected from pyrrolidine and piperidine, wherein the ring is fusedto phenyl.
 31. The compound of claim 30, represented by the followingstructural formula:

or a pharmaceutically acceptable salt thereof.
 32. The compound of claim26, wherein: the (4-7 membered) monocyclic heterocylic ring, or a (6-13membered) bicyclic heterocylic ring, wherein the (4-7 membered)monocyclic heterocylic ring, or the (6-13 membered) bicyclicheterocyclic ring is substituted with at least one substituentindependently selected from C₃-C₁₀ carbocyclyl, (4-13 membered)heterocyclyl, and is optionally substituted with one or moresubstituents independently selected from fluoro, —OH, —C₁-C₃ alkyl and—C₁-C₃ alkylene-O—C₁-C₃ alkyl.
 33. The compound of claim 32, wherein:the R² and R³ taken together with the nitrogen atom to which they arebound form a ring selected from pyrrolidine, piperidine, piperazine ormorpholine.
 34. The compound of claim 33, wherein: the C₃-C₁₀carbocyclyl is a phenyl.
 35. The compound of claim 34, wherein R² and R³taken together with the nitrogen atom to which they are bound form aring selected from pyrrolidine and piperidine.
 36. The compound of claim35, wherein X is fluoro.
 37. The compound of claim 36, represented bythe following structural formula,

or a pharmaceutically acceptable salt thereof.
 38. A pharmaceuticalcomposition comprising a pharmaceutically acceptable carrier or diluentand a compound of claim
 1. 39. A method for treating cancer in a subjectin need thereof, comprising administering to the subject an effectiveamount of the composition of claim 38, wherein the cancer is coloncancer, ovarian cancer, or kidney cancer.